Nasolacrimal implants and related methods for tear stimulation

ABSTRACT

A device for inducing production of tears may include a body extending from a proximal end to a distal end. The body may be configured for insertion through a puncta of a subject. The device also may include a stimulus delivery mechanism positioned between the proximal end and the distal end and an induction coil operably coupled to the stimulus delivery mechanism. Further, the device may include an external controller wirelessly coupled to the induction coil for inductively transferring energy to the induction coil.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefits of priority from U.S. ProvisionalApplication No. 62/321,961, filed Apr. 13, 2016, and U.S. ProvisionalApplication No. 62/180,265, filed Jun. 16, 2015, each of which isincorporated by reference herein in its entirety.

TECHNICAL FIELD

Various aspects of the present disclosure relate generally to medicalsystems, devices, and related methods. More specifically, the presentdisclosure relates to devices, systems, and methods for performingtherapies within a subject for the inducement of tear production via,e.g., nasolacrimal tissue stimulation.

BACKGROUND

Dry Eye Disease (“DED”) is a condition that affects millions of peopleworldwide. The etiology of DED is becoming increasingly well understood.DED is progressive in nature, and results from the disruption of thenatural tear film on the surface of the eye (e.g., the ocular surface).Such disruption may prevent healthy gas exchange and nutrient transportfor the ocular surface, promote cellular desiccation, and/or may createa poor refractive surface for vision. The disruption of the natural tearfilm typically results from one or more of 1) insufficient aqueous tearproduction from the lacrimal glands (e.g., caused by secondary topost-menopausal hormonal deficiency, auto-immune disease, LASIK surgery,etc.), and/or 2) excessive evaporation of aqueous tears resulting fromdysfunction of the meibomian glands. Low tear volume may cause ahyperosmolar environment that may induce an inflamed state of the ocularsurface. This inflammatory response may induce apoptosis of ocularsurface cells which in turn prevent proper distribution of the tear filmon the ocular surface. Accordingly, any available tear volume deliveredto the ocular surface may be rendered less effective. This may initiatea vicious cycle in which more inflammation can ensue, causing moreocular surface cell damage, etc. Additionally, the neural control loop,which controls reflex tear activation, may be disrupted because thesensory neurons in the ocular surface are damaged. As a result, fewertears may be secreted and a second vicious cycle may develop thatresults in further progression of the disease (e.g., fewer tears maycause nerve cell loss, which may result in even fewer tears, etc.)

DED can result in ocular discomfort, visual disturbance, and/or areduction in vision-related quality of life. Activities such as, e.g.,driving, computer use, housework, and reading are often negativelyimpacted by DED. Subjects with severe cases of DED are at risk forserious ocular health deficiencies such as, e.g., corneal ulceration,and can experience a quality of life deficiency comparable to that ofmoderate to severe angina.

There is a wide spectrum of treatments for DED including: artificialtear substitutes, ointments, gels, warm compresses, environmentalmodification, topical cyclosporine, omega-3 fatty acid supplements,punctal plugs, moisture chamber goggles, punctal cautery, systemiccholinergic agonists, systemic anti-inflammatory agents, mucolyticagents, autologous serum tears, PROSE scleral contact lenses, andtarsorrhaphy. While current treatment options for DED are numerous, suchtreatment options have limited effectiveness and generally provide onlymild symptom relief or improvement in ocular health over a short periodof time.

The systems, devices, and methods of the current disclosure may rectifysome of the deficiencies described above or address other aspects of theprior art.

SUMMARY

Aspects of the present disclosure relate to, among other things,nasolacrimal tissue stimulation. Each of the examples disclosed hereinmay include one or more the features described in connection with any ofthe other disclosed examples.

In one example, a device for inducing production of tears may include abody extending from a proximal end to a distal end. The body may beconfigured for insertion through a puncta of a subject. Additionally,the device may include a stimulus delivery mechanism positioned betweenthe proximal end and the distal end.

Examples of the device may additionally include one or more of thefollowing features. The stimulus delivery mechanism may include aconductor. The device may additionally include a plurality of conductorspositioned between the proximal end and the distal end of the body. Aninduction coil may be operably coupled to the stimulus deliverymechanism. The body may be configured for direct contact with acanaliculus of a subject. The device may further include a faceplateadjacent the proximal end of the body. The device may further include asensor configured for sensing one or more of biochemical properties oftears, placement of the body, and operation of stimulus deliverymechanism.

In one example, a device for inducing production of tears may include abody extending from a proximal end to a distal end. The body may beconfigured for insertion through a puncta of a subject. The device alsomay include a stimulus delivery mechanism positioned between theproximal end and the distal end and an induction coil operably coupledto the stimulus delivery mechanism. Further, the device may include anexternal controller wirelessly coupled to the induction coil forinductively transferring energy to the induction coil.

Examples of the device may additionally include one or more of thefollowing features. The body may include an opening extending through aside wall of the body. At least a portion of the stimulus deliverymechanism may be positioned within the opening. The body may include aplurality of openings extending through a side wall of the body. Thestimulus delivery mechanism may include a conductor. A plurality ofconductors may be positioned between the proximal end and the distal endof the body. A faceplate may be adjacent the proximal end of the body.The faceplate may have a faceplate diameter larger than a diameter ofthe proximal end of the body. The induction coil may be in directcontact with the faceplate. The body and the faceplate may includenon-planar surfaces. The body may be tapered such that the proximal endmay have a proximal end diameter and the distal end may have a distalend diameter, and the distal end diameter may be smaller than theproximal end diameter. A lumen may extend from the proximal end of thebody to the distal end of the body. The body may include mesh. The meshmay be self-expandable. A sensor may be configured for sensing one ormore of biochemical properties of tears, placement of the body, andoperation of stimulus delivery mechanism.

In a further example, a method for inducing production of tears mayinclude contacting tissue of a canaliculus of a subject with a stimulusdelivery mechanism of a device. The method may further includewirelessly communicating a stimulation signal from an external device toan induction coil associated with the device. Further, the method mayinclude stimulating tissue of the canaliculus of the subject via thestimulation delivery mechanism to induce tearing from a lacrimal glandof the subject.

Examples of the method may additionally include one or more of thefollowing features. Additionally, the method may include inserting thedevice through a puncta of the subject and positioning the device withinthe canaliculus of the subject. Upon inserting the device andpositioning the device, no portion of the device may be received withina nasal cavity of the subject. Stimulating tissue of the canaliculus ofthe subject may include exciting at least one of the nasociliary nerve,the supratrochlear nerve, and the infratrochlear nerve to induce tearingfrom the lacrimal gland of the subject.

In a further example, a system for inducing production of tears mayinclude a plurality of stimulation devices. Each stimulation device mayinclude a body extending from a proximal end to a distal end, a stimulusdelivery mechanism positioned between the proximal end and the distalend, and an induction coil operably coupled to the stimulus deliverymechanism. The system also may include an external controller wirelesslycoupled to the induction coil of each of the plurality of stimulationdevices for inductively transferring energy to the induction coil.Further, the placement of at least one stimulation device of theplurality of stimulation devices may be dependent on the placement of atleast one other stimulation device of the plurality of stimulationdevices.

In a further example, at least one device for stimulating the lacrimalsystem may include a stimulator body having at least one power sourceand a control subsystem with a distal end bio-stimulus transducer inelectronic communication with the control subsystem. The controlsubsystem may include at least logic and communication circuits. The atleast one device may include a proximal end faceplate. The faceplate mayinclude at least one sensor and at least one antenna in electroniccommunication with the control subsystem.

Additionally, the at least one device may include one or more of thefollowing features. The stimulator body may further include an isolationcoupling between the control subsystem and the bio-stimulus transducer.The power source may include a battery. The logic and communicationcircuits may receive specific stimulus programming instructions throughthe antenna. The antenna may provide a wireless link between the controlsubsystem and at least one wireless device. The wireless device mayinclude a computer, a smartphone, a tablet, a smart watch, or the like.The medical device may be controlled through the wireless device througha program application or “app.” The battery may be rechargeable. Theisolation coupling may be a vibration-dampening element. The controlsubsystem may further include memory to store operational data from thestimulator and configured to retrieve data from the antenna. The sensorsmay evaluate conductivity. The sensor may be a molecular sensor. Thesensor may be a biological sensor. The antenna may be a communicationantenna. The antenna may further include a radio frequency (RF) poweramplifier. At least the distal end of the device may include a flexibleouter stimulator body. The stimulator body may include an expandablecomponent. The stimulator body may include a helical outer wall. Thehelical outer wall may be configured to expand vertically. The helicalouter wall may be configured as a horizontal anchor. The stimulustransducer may further include multiple zones comprising electrodes. Theelectrical stimulation may include a biphasic pulse waveform. Thebiphasic pulse waveform may be symmetrical. The frequency of thebiphasic pulse waveform may be between about 20 Hz and about 80 Hz. Thestimulator body may further include at least one distal end magneticcomponent. The stimulator body may further include at least one distalend magnetic component with magnetic attraction to a second device. Thesecond device may include another stimulator device. The bio-stimulustransducer may include at least one vibration element. The vibrationelement may be a sonic element. The vibration element may be anultrasonic element. The bio-stimulus transducer may include at least onethermal element. The thermal element may include a heating element. Thethermal element may include a cooling element. The bio-stimulustransducer may include at least one mechanical element. The stimulatorbody may further include a central drainage lumen. At least the distalend of the device may include a flexible outer stimulator body.

In a further example, a device for stimulating the lacrimal system mayinclude a stimulator body having a power source and a control subsystemwith a distal end bio-stimulus transducer in electronic communicationthe control subsystem. The power source may include a battery and thecontrol subsystem may include at least logic and communication circuits.Additionally the device may include a proximal end faceplate. Thefaceplate may include at least one sensor and at least one antenna inelectronic communication with the control subsystem. In one example, thestimulator body may further include an isolation coupling between thecontrol subsystem and the bio-stimulus transducer. In one example, thebattery may be rechargeable. In one example, the isolation coupling maybe a vibration-dampening element. In one example, the control subsystemmay further include a memory to store operational data from thestimulator and may be configured to retrieve data from the antenna. Inone example, the sensors may evaluate conductivity. The sensor may be amolecular sensor. The sensor may be a biological sensor. The antenna maybe a communication antenna. The antenna may further include a radiofrequency (RF) power amplifier. At least the distal end of the devicemay include a flexible outer stimulator body. The bio-stimulustransducer may further include multiple zones comprising electrodes. Thestimulator body may further include at least one distal end magneticcomponent. The stimulator body may further include at least one distalend magnetic component that pairs with a second device. The seconddevice may include another stimulator device. The bio-stimulustransducer may include at least one vibration element. The bio-stimulustransducer may include at least one thermal element. The thermal elementmay include a heating element. The thermal element may include a coolingelement. The bio-stimulus transducer may include at least one mechanicalelement.

In a further example, a method for treating a condition of an eye of asubject may include providing a subject including a lacrimal system anda lacrimal system stimulation device. The device may include astimulator body including a power source and a control subsystem with adistal end bio-stimulus transducer. The bio-stimulus transducer may becapable of inducing reflex tear activation within the subject, and maybe in electronic communication with the control subsystem. The powersource may include a battery and the control subsystem may include atleast logic and communication circuits. The device may further include aproximal end faceplate including at least one sensor and at least oneantenna in electronic communication with the control subsystem. Themethod may further include implanting the distal end of the device intoa punctum of the lacrimal system such that the bio-stimulus transducercontacts the mucosal tissues of the lacrimal system and the proximal endfaceplate contacts the punctum opening. The method also may includestimulating at least one site of the subject with the device so as toinduce reflex tear activation. One site of the subject may include themucosa of the lacrimal sac. One site of the subject may include themucosa of the upper region of the nasolacrimal duct. One site of thesubject may include the mucosa of the tear drainage system. Thestimulating may include electrical stimulation. The stimulating mayinclude mechanical stimulation. The stimulating may include chemicalstimulation. The stimulating may include thermal stimulation. Theexpandable component may be expanded through a faceplate port by theinjection of a substance to expand the expandable component(s) in thedevice. The expansion components may be used to enhance retention of thedevice in the tear drainage system and/or to enhance contact of theexternal surface of the device with surrounding mucosa. The stimulatorbody may include a helical outer wall. The helical outer wall may beconfigured to expand vertically. The helical outer wall may beconfigured as a horizontal anchor. The helical outer wall may enhancefixation of the device in the lumen of the punctum and canaliculisystem. The helical outer wall may unwind once placed in the lumen ofthe punctum and canalicular system so that the helical outer wall mayact as an anchor against the mucosa of the tear drainage system.

In a further example, a method for treating a condition of an eye of asubject may include stimulating at least one site of the subject, so asto treat the eye condition. The site may be selected from the groupconsisting of: at least one area of the mucosa of the upper region ofthe nasolacrimal duct of the subject, at least one area of the mucosa ofthe lacrimal sac of the subject, at least one area of the tear drainagesystem mucosa of the subject, and a conjunctiva and/or caruncle of themedial canthus of the subject. Stimulating the site may includestimulating to induce reflex tear activation, so as to treat the eyecondition. The eye condition may include dry eye.

Further examples include devices, systems, and methods for treating oneor more conditions (such as dry eye) by providing stimulation to thenasolacrimal system and/or the surrounding mucosa and adjacentstructures. The devices and systems may be configured to stimulate thenasolacrimal system and/or the surrounding mucosa and adjacentstructures. The devices may be implantable and may be disposable and/orbiodegradable. The implant may reside in the nasolacrimal system (e.g.,for example, punctum, canaliculi, nasolacrimal sac, nasolacrimal duct)and outside of the nasal cavity. The device may provide stimulus to thesurrounding mucosa through vibrational energy (e.g., for example, sonic,ultrasonic, etc.) or through other stimuli such as high or lowtemperatures, mechanical stretch and relaxation or delivery of moleculesthat stimulate the surrounding mucosa and adjacent structures. Thestimulus may induce a reflex arc through the nasociliary nerve to inducetearing from the lacrimal gland. The stimulus may be provided directlyto the caruncle and/or conjuctiva of the medial canthus. The stimulusmay be delivered on command through remote sensor communication. Thestimulus may be programmed to deliver the stimulus on a specificpre-programmed schedule. The device may be removable via a minimallyinvasive procedure. The implant resides within the tear excretorypathway (punctum to nasolacrimal duct) which possess the capability tostimulate the mucosa of the lacrimal sac and upper region of thenasolacrimal duct (innervated by infra-trochlear nerve a terminal branchof V1) and which leads to reflex tearing of the lacrimal gland whichalso innervated by V1. The stimulatory process may be through sonic,ultrasonic, mechanical, chemical, light or other means which may inducenerve response from the region of the lacrimal sac and nasolacrimalduct. The devices may include a stimulator body containing at least onebio-stimulus transducer or stimulator. The stimulus delivered by thestimulators described herein may be electrical, mechanical, thermal,chemical, light-based, magnetic, or the like. When the devices andsystems are used to treat dry eye, the methods disclosed herein mayinclude stimulating mucosa of the lacrimal sac and upper region of thelacrimal duct to increase tear production, reduce the symptoms of dryeye, and/or improve ocular health. The methods may further includetreating dry eye by regular activation of the nasolacrimal reflex.

Further examples may include one or more devices for stimulating mucosaof the lacrimal sac and upper region of the nasolacrimal duct of asubject. The device may include a stimulator body and a bio-stimulustransducer connected to the stimulator body. The stimulator body mayinclude a control subsystem to control a stimulus to be delivered to thesubject via the bio-stimulus transducer. The bio-stimulus transducer mayinclude at least the distal end of the device. The bio-stimulustransducer may include at least one electrode. The stimulus may beelectrical. The electrode may include a hydrogel. The electrode mayinclude one or more of platinum, copper, platinum-iridium, gold, orstainless steel. The stimulus may be a biphasic pulse waveform. Thebiphasic pulse waveform may be symmetrical. The frequency of thebiphasic pulse waveform may be between about 20 Hz and about 80 Hz. Thebio-stimulus transducer may be releasably connected to the stimulatorbody. The stimulator body may be reusable and the bio-stimulustransducer may be disposable. The device may include a user interface.The user interface may include one or more operating mechanisms toadjust one or more parameters of the stimulus. Additionally oralternatively, the user interface may include one or more feedbackelements. The feedback elements may include haptic feedback elements.

The devices described herein may include systems for stimulating mucosaof the lacrimal sac and upper region of the nasolacrimal duct of asubject. The device may include a stimulator having a bio-stimulustransducer and a stimulator body including a power source and a controlsubsystem to control a stimulus to be delivered to the subject via thebio-stimulus transducer. The power source may include a battery. Thepower source may be rechargeable. The device may include a controlsubsystem. The control subsystem may include a battery, and logic andcommunication circuits. The device may include an isolation coupling.The battery may be rechargeable. The isolation coupling may be avibration-dampening element. The stimulator may include memory to storedata configured to retrieve data from the stimulator. The device mayinclude a proximal faceplate. The faceplate may include sensors. Thesensors may evaluate conductivity. The sensor may be a molecular sensor.The sensor may be a biological sensor. The faceplate may include anantenna. The antenna may be a communication antenna. The antenna mayinclude a radio frequency (RF) power amplifier. The sensor may beelectronically connected to the logic and communication circuits. Theantenna may be electronically connected to the logic and communicationcircuits. The bio-stimulus transducer may be electronically connected tothe logic and communication circuits. The stimulator body may include acentral drainage lumen. At least the distal end of the device mayinclude a flexible outer stimulator body. The stimulator body mayinclude multiple zones comprising electrodes. The stimulator body mayinclude at least one distal end magnetic component. The stimulator bodymay include at least one distal end magnetic component that pairs with asecond device. The second device may include another stimulator device.

In a further example, a method of tear production in a subject mayinclude implantation of a medical device into the lacrimal gland throughat least one punctum of the subject. The medical device may include astimulator body having a faceplate, a bio-stimulus transducer, a powersource and a control subsystem to control a stimulus to be delivered tothe subject via the bio-stimulus transducer. The method may includepositioning the bio-stimulus transducer in contact with the lacrimalsystem mucosa of the subject, and delivering a stimulus via thebio-stimulus transducer to produce tears. The lacrimal system mucosa mayinclude the mucosa of the lacrimal sac and upper region of thenasolacrimal duct. The method may include positioning a secondbio-stimulus transducer in contact with the lacrimal system mucosa ofthe subject. The stimulus may be electrical. The stimulus may bedelivered for a 1 second to 5 minute period, and the Schirmer score overthe 5 minute period may be at least 3 mm greater than a basal Schirmerscore of the patient. In some of these variations, the Schirmer scoreover the 5 minute period may be at least 5 mm greater than a basalSchirmer score of the patient. The stimulus may be a biphasic pulsewaveform. The biphasic pulse waveform may be symmetrical. The stimulusmay be pulsed. The method may include positioning a bio-stimulustransducer in contact with the lacrimal system mucosa of the subject anddelivering a stimulus via the bio-stimulus transducer to produce tearson a second occasion. The stimulus may be mechanical. The stimulus maybe chemical.

In further examples, a method of improving ocular health in a patientmay include positioning a bio-stimulus transducer in a lacrimal systemof the patient, and delivering stimulation to the mucosa of the lacrimalsac and upper region of the nasolacrimal duct of the patient via thebio-stimulus transducer at least once daily during a treatment periodincluding at least 2 days to improve the ocular health of the patient,wherein improved ocular health may be measured by decreased dry eyesymptoms. The bio-stimulus transducer may include at least oneelectrode, and the stimulation may be electrical. In one example,decreased dry eye symptoms may be measured by the Ocular Surface DiseaseIndex, and the Ocular Surface Disease Index may decrease by at least 10%within the treatment period, wherein the treatment period may include 7days. The Ocular Surface Disease Index may decreases by at least 20%within the treatment period. Decreased dry eye symptoms may be measuredby the Ocular Surface Disease Index, and the Ocular Surface DiseaseIndex may decrease by at least 40% within the treatment period, whereinthe treatment period may include 90 days. The Ocular Surface DiseaseIndex may decrease by at least 50% within the treatment period. Thestimulation may activate the nasolacrimal reflex. The bio-stimulustransducer may be positioned in contact with lacrimal system mucosa ofthe patient. The bio-stimulus transducer may be positioned in contactwith lacrimal system mucosa of the patient. The bio-stimulus transducermay include at least one electrode. The electrical stimulation mayinclude a biphasic pulse waveform. The biphasic pulse waveform may besymmetrical. The frequency of the biphasic pulse waveform may be betweenabout 20 Hz and about 80 Hz. The stimulation may be mechanical. Thestimulation may be chemical. The stimulation may be thermal.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate exemplary aspects of the presentdisclosure and together with the description, serve to explain theprinciples of the disclosure. The drawings are only for the purpose ofillustrating aspects of the disclosure and are not to be construed aslimiting the disclosure.

FIG. 1 illustrates a side-view of an eye of a subject, depicting thethree layers of naturally produced tears;

FIG. 2 illustrates anatomical features of nerves and blood vesselsrelated to the eye and lacrimal system of a subject;

FIG. 3 illustrates anatomical features related to the eye and lacrimalsystem of a subject;

FIGS. 4 and 5 illustrate exemplary stimulators according to aspects ofthe current disclosure;

FIGS. 6-9 illustrate further exemplary stimulators according to aspectsof the current disclosure;

FIG. 10 illustrates the exemplary stimulator of FIG. 9 positioned withinthe lacrimal system of a subject;

FIGS. 11 and 12 illustrate further exemplary stimulators according toaspects of the current disclosure; and

FIG. 13 illustrates a plurality of stimulators positioned within thelacrimal system of the subject.

It may be understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restriction of the disclosure.

As used herein, the terms “comprises,” “comprising,” or any othervariation thereof, are intended to cover a non-exclusive inclusion, suchthat a process, method, article, or apparatus that comprises a list ofelements does not include only those elements, but may include otherelements not expressly listed or inherent to such process, method,article, or apparatus. The term “exemplary” is used in the sense of“example,” rather than “ideal.”

DEFINITIONS

To facilitate the understanding of this disclosure, a number of termsare defined below. Terms defined herein have meanings as commonlyunderstood by a person of ordinary skill in the areas relevant to thepresent disclosure. Terms such as “a,” “an,” and “the” are not intendedto refer to only a singular entity, but include the general class ofwhich a specific example may be used for illustration. The terminologyherein is used to describe specific examples of the disclosure, buttheir usage does not limit the disclosure.

As used herein, the term “patient” or “subject” refers to any living ornon-living mammalian organism, such as a human, monkey, cow, sheep,goat, dog, cat, mouse, rat, guinea pig, and/or transgenic speciesthereof. In certain aspects, the patient or subject may be a primate.Non-limiting examples of human subjects are adults, juveniles, infants,and fetuses.

“Prevention” or “preventing” as used herein, includes, but is notlimited to: (1) inhibiting the onset of a disease (e.g., DED) in asubject or patient which may be at risk and/or predisposed to thedisease, wherein such inhibition may be either partial or complete, butdoes not yet experience or display any or all of the pathology orsymptomatology of the disease, and/or (2) slowing the onset of thepathology or symptomatology of a disease in a subject or patient whichmay be at risk and/or predisposed to the disease but does not yetexperience or display any or all of the pathology or symptomatology ofthe disease.

As used herein, the term “ocular health” refers to restoring ormaintaining a physiologically normal (e.g., healthy) amount, level,and/or degree of tears in the eye to minimize or alleviate dryness andrelated discomfort and to maintain eye health. Such minimization and/oralleviation of dryness may treat or prevent at least one symptomassociated with DED such as, e.g., stinging, burning, and/or scratchysensation in the eyes; stringy mucus in or around an eye; increased eyeirritation from smoke or wind; eye fatigue; eye sensitivity to light;eye redness; a sensation of having something in your eyes; difficultywearing contact lenses; periods of excessive tearing; and blurredvision, often worsening at the end of the day or after focusing for aprolonged period.

“Therapeutically effective amounts” and “pharmaceutically effectiveamounts,” as used herein, indicate that amount which, when administeredto a subject or patient for treating a disease, is sufficient to effectsuch treatment for the disease or to ameliorate one or more symptoms ofthe disease or condition (e.g., ameliorate pain).

As used herein, the terms “treat,” “treating,” and/or “treatment” arenot limited to cases in which the subject (e.g., patient) is cured andthe disease is eradicated. Rather, treatment also may merely reducesymptoms, improve (to some degree) a condition of the patient and/orsubject, and/or delay disease progression, among other effects. It isnot intended that treatment be limited to instances wherein a disease oraffliction is cured. It is sufficient that symptoms are reduced.

As used herein, the terms “medical device,” “implant,” “device,”“medical implant,” “implant/device,” and the like are used synonymouslyto refer to any object that is designed to be placed partially or whollywithin a patient's body for one or more therapeutic or prophylacticpurposes such as, e.g., for tissue augmentation, tissue stimulation,contouring, restoring physiological function, repairing and/or restoringtissues damaged by disease or trauma, and/or delivering therapeuticagents to normal, damaged, and/or diseased organs and tissues. Whilemedical devices are often composed of biologically compatible syntheticmaterials (e.g., medical-grade stainless steel, nitinol, titanium,and/or other metals; exogenous polymers, such as polyurethane, silicone,PLA, PLGA, PGA, PCL, etc.), other materials also may be used in theconstruction of the medical implant. While not limiting the presentdisclosure to any particular device, specific medical devices andimplants that are particularly relevant to this disclosure includestents, punctal plugs, Crawford tubes, catheters, lacrimal tubes, ocularor other shunts. In some examples, the device may incorporate a contrastmaterial and/or opaque material(s) that may allow for visualization withstandard imaging devices (for example, barium to allow for x-rayvisualization).

As used herein, the term “proximal” refers to a location situated and/orpositioned toward a point of origin (e.g., between a physician and alacrimal implant device). In other words, the term “proximal” may referto a position relatively closer to the exterior of the body of thepatient or subject, and/or closer to an operator, physician, or medicalprofessional.

As used herein, the term “distal” refers to a location situated and/orpositioned away from a point of origin (e.g., behind a lacrimal implantdevice relative to a physician). In other words, the term “distal” mayrefer to a position relatively further away from the operator,physician, or medical professional, or closer to the interior of thebody of the patient or subject.

As used herein, the term “implanted” refers to a state in which a deviceis completely or partially placed within a host. A device is partiallyimplanted when some of the device reaches, or extends to the outside of,a host.

As used herein, the term “biomaterial” refers to any substance (otherthan drugs) or combination of substances synthetic or natural in origin,which can be used for any period of time, as a whole or as a part of asystem which treats, augments, or replaces any tissue, organ, orfunction of the body.

As used herein, the term “biocompatibility” refers to the ability of amaterial to perform with an appropriate host response in a specificapplication.

As used herein, the terms “tear drainage system,” “nasolacrimal drainagesystem,” and “lacrimal drainage system,” refer to any connectedanatomical structures having two small openings (e.g., for example,puncta). For example, a puncta may be located in an upper and/or lowereyelid, wherein these small openings lead into a small tube (e.g., forexample, a canaliculus) which, in turn, empties into a lacrimal sac 16and then into a canal called the nasolacrimal duct 18 (FIG. 2).

As used herein, the term “vibrating element” refers to a device partthat changes electrical energy into mechanical or vibrational energy andtransfers the vibrational energy, directly or indirectly, to avibratable member. For example, piezoelectric substances are typicallypolarized crystalline materials which may transform electrical energyinto mechanical energy. Piezoelectric materials also may emitvibrational waves in a variety of particular directions. Ceramicpiezoelectric materials such as lead zirconium niobate are also useful.

As used herein, the term “sonic element” refers to a vibrating elementdevice part which is capable of producing sound waves. Sonic devicesgenerally operate between about 20 Hz and about 20 kHz.

As used herein, the term “ultrasonic element” refers to a vibratingelement device part which is capable of producing ultrasonic soundwaves. Ultrasound devices operate with frequencies from about 20 kHz toabout several gigahertz.

DESCRIPTION Overview Dry Eye Syndrome

Dry eye is a condition in which there are insufficient tears tolubricate and nourish the eye. Tears are necessary for maintaining thehealth of the front surface (e.g., cornea, the ocular surface) of theeye and for providing clear vision. People with dry eyes either do notproduce enough tears or have a poor quality of tears. Dry eye is acommon and often chronic problem, particularly in older adults. Tsubota,K. (1998) “Tear Dynamics and Dry Eye,” Prog. Retin. Eye Res 17(4),565-596, describes the dry eye condition in greater detail and isincorporated by reference herein.

With each blink of the eyelids, tears are spread across the frontsurface of the eye, known as the cornea. Tears provide lubrication,reduce the risk of eye infection, wash away foreign matter in the eye,and keep the surface of the eyes smooth and clear. Excess tears in theeyes flow into small drainage ducts, in the inner corners of theeyelids, which drain in the back of the nose. Dry eyes can result froman improper balance of tear production and drainage.

Inadequate amount of tears—Tears are produced by several glands in andaround the eyelids. Tear production tends to diminish with age, withvarious medical conditions, or as a side effect of certain medicines orprocedures. Environmental conditions such as wind and dry climates canalso affect tear volume by increasing tear evaporation. When the normalamount of tear production decreases or tears evaporate too quickly fromthe eyes, symptoms of dry eye can develop.

Poor quality of tears—As discussed in further detail below, tears aremade up of three layers: oil, water, and mucus. Each layer serves afunction in protecting and nourishing the front surface of the eye. Asmooth oil layer helps to prevent evaporation of the water layer, whilethe mucin layer functions in spreading the tears evenly over the surfaceof the eye. If the tears evaporate too quickly or do not spread evenlyover the cornea due to deficiencies with any of the three tear layers,dry eye symptoms can develop.

The most common form of dry eyes is due to an inadequate amount of thewater layer of tears. This condition, called keratoconjunctivitis sicca(KCS), is also referred to as dry eye syndrome.

People with dry eyes may experience symptoms of irritated, gritty,scratchy, or burning eyes, a feeling of something in their eyes, excesswatering, and blurred vision. Advanced dry eyes may damage the frontsurface of the eye and impair vision.

Treatments for dry eyes aim to restore or maintain the normal amount oftears in the eye to minimize dryness and related discomfort and tomaintain eye health.

What Causes Dry Eyes?

The majority of people over the age of 65 experience some symptoms ofdry eyes. The development of dry eyes can have many causes. Theyinclude:

Age—Dry eye is a part of the natural aging process. The majority ofpeople over age 65 experience some symptoms of dry eyes.

Dehydration—Lack of proper hydration may result in poor tear production.

Hormonal deficiencies or changes and Gender—Thyroid conditions, hormonalchanges during menopause, decreased production of androgen, estrogensupplementation (there are reports both of this improving dry eyeconditions and worsening them), and women are more likely to develop dryeyes due to hormonal changes caused by pregnancy, the use of oralcontraceptives, and menopause.

Medications—Certain medicines, including antihistamines, decongestants,blood pressure medications, allergy medications, antidepressants, (e.g.amitriptyline, diazepam), parkinson's medications, birth control pills,diuretics, beta blockers, sleeping pills, many pain medications, andcertain medications which regulate heart rhythm irregularities, canreduce the amount of tears produced in the eyes.

Medical conditions—Persons with rheumatoid arthritis, diabetes andthyroid problems are more likely to have symptoms of dry eyes. Also,problems with inflammation of the eyelids (blepharitis), inflammation ofthe surfaces of the eye, or the inward or outward turning of eyelids cancause dry eyes to develop. Corneal ulcers and infections, eyeinfections, such as conjunctivitis.

Other conditions—Vitamin A deficiency, secondary tearing deficiency(associated with disorders such as—lymphoma, leukemia, GVHD (graft vs.host disease, after a transplant), and rheumatoid arthritis),Parkinson's disease, Sjögren's syndrome (an auto-immune disease),Rheumatoid arthritis, Lupus, Lacrimal gland deficiency, Diabetes,Sarcoidosis, Stevens-Johnson syndrome, and Rosacea: Facial rosacea iscommonly associated with ocular rosacea, which causes conditions such asblepharitis.

Environmental conditions—Exposure to smoke, wind, dry climates, highaltitudes, excessive sun exposure, central heating, air conditioning,hair dryers, cigarette smoke, air pollution, and air travel can increasetear evaporation resulting in dry eye symptoms. Failure to blinkregularly, such as when staring at a computer screen for long periods oftime, can also contribute to drying of the eyes.

Low blink rate—Blinking is critical in spreading tears over the surfaceof the eye and stimulating tear production. A chronic low blink rate isassociated with dry eye symptoms. Computer use, reading, and watching TVare the three activities most commonly associated with a low blink rate.

Other factors—Long-term use of contact lenses can be a factor in thedevelopment of dry eyes. Refractive eye surgeries, such as LASIK, cancause decreased tear production and dry eyes. A temporary or permanentside effect of LASER vision correction surgery such as LASIK orphotorefractive keratectomy (PRK).

How are Dry Eyes Diagnosed?

Dry eyes can be diagnosed through a comprehensive eye examination.Testing, with special emphasis on the evaluation of the quantity andquality of tears produced by the eyes, may include: Patient history todetermine any symptoms the patient is experiencing and the presence ofany general health problems, medications taken, or environmental factorsthat may be contributing to the dry eye problem. External examination ofthe eye, including lid structure and blink dynamics. Evaluation of theeyelids and cornea using bright light and magnification. Measurement ofthe quantity and quality of tears for any abnormalities. Special dyesmay be instilled in the eyes to better observe tear flow and tohighlight any changes to the outer surface of the eye caused byinsufficient tears.

Schirmer's Test

Schirmer's test determines whether the eye produces enough tears to keepit moist. This test is used when a person experiences very dry eyes orexcessive watering of the eyes. It poses no risk to the subject. Anegative (more than 10 mm of moisture on the filter paper in 5 minutes)test result is normal. Both eyes normally secrete the same amount oftears.

Schirmer's test uses paper strips inserted into the eye for severalminutes to measure the production of tears. The exact procedure may varysomewhat. Both eyes are tested at the same time. Most often, this testconsists of placing a small strip of filter paper inside the lowereyelid (inferior fornix). The eyes are closed for 5 minutes. The paperis then removed and the amount of moisture is measured. Sometimes atopical anesthetic is placed into the eye before the filter paper toprevent tearing due to the irritation from the paper. The use of theanesthetic ensures that only basal tear secretion is being measured.This technique measures basic tear function.

A young person normally moistens 15 mm of each paper strip. Becausehypolacrimation occurs with aging, 33% of normal elderly persons may wetonly 10 mm in 5 minutes. Persons with Sjögren's syndrome moisten lessthan 5 mm in 5 minutes.

Alternatives to Schirmer's test

Even though this test has been available for over a century, severalclinical studies have shown that it does not properly identify a largegroup of patients with dry eyes. Newer and better tests of tearproduction and function are now emerging.

One test measures an iron-binding molecule called lactoferrin. Theamount of this molecule appears to be closely related to tearproduction. Patients with low tear production and dry eyes have lowlevels of this molecule. This test may be especially valuable forpatients with dry eyes since it can point to specific treatmentstrategies for dry eye.

The tears also may be examined for their content of lysozyme, an enzymenormally found in tears.

Another test involves fluorescein eye drops, which contain a dye that isplaced in the eye. The dye should drain with the tears through thelacrimal duct into the nose within 2 minutes. If patients do not haveenough tears to flush the dye into the nose, this time will be longer. Anew test is also available to more accurately measure the flow of dyeout of the eye.

Reflex Tearing

Reflex tearing is produced by strong physical or emotional stimulationof the lacrimal gland. The tears thus produced contain essentialcomponents, such as vitamin A and EGF, for the proliferation anddifferentiation of the corneal and conjunctival epithelium. Even ifbasic tearing is decreased, accelerating desiccation of the ocularsurface, if reflex tears are present, they can provide the ocularsurface epithelium with substances necessary for proper epithelial woundhealing.

The Schirmer test without topical anesthesia, in which the test stripstimulates the cornea, conjunctiva and lid margin, has generally beenused to measure reflex tearing. However, a result of 0 mm does notnecessarily mean that the patient is incapable of producing reflextears. Schirmer described the measurement of reflex tearing bystimulating the nasal mucosa with a camel's hair brush afteranesthetizing the ocular surface with 4% cocaine. To check maximalreflex tearing, the Schirmer II test can be modified by using a cottonswab to stimulate the nasal mucosa without any anesthetic. Although theSchirmer II test is rarely used because either reflex tearing is assumedto be intact or the regular Schirmer test is considered more accurate,certain dry eye patients have been seen who are incapable of reflextearing, and for whom the stimulate the nasal mucosa without anyanesthetic is an important test.

How are Dry Eyes Treated?

One of the primary approaches used to manage and treat mild cases of dryeyes is adding tears using over-the-counter artificial tear solutions.

Dry eyes can be a chronic condition, but your optometrist can prescribetreatment to keep your eyes healthy, more comfortable, and prevent yourvision from being affected. The primary approaches used to manage andtreat dry eyes include adding tears, conserving tears, increasing tearproduction, and treating the inflammation of the eyelids or eye surfacethat contributes to the dry eyes.

Adding tears—Mild cases of dry eyes can often be managed usingover-the-counter artificial tear solutions. These can be used as oftenas needed to supplement natural tear production. Preservative-freeartificial tear solutions are recommended because they contain feweradditives that could further irritate the eyes. However, some people mayhave persistent dry eyes that don't respond to artificial tears alone.Additional steps may need to be taken to treat their dry eyes.

Conserving tears—An additional approach to reducing the symptoms of dryeyes is to keep natural tears in the eyes longer. This can be done byblocking the tear ducts through which the tears normally drain. The tearducts can be blocked with tiny silicone or gel-like plugs that can beremoved, if needed. A surgical procedure to permanently close tear ductscan also be used. In either case, the goal is to keep the availabletears in the eye longer to reduce problems related to dry eyes.

Increasing tear production—An optometrist may recommend prescription eyedrops that help to increase production of tears, as well as omega-3fatty acid nutritional supplements.

Treatment of the contributing eyelid or ocular surfaceinflammation—Prescription eye drops or ointments, warm compresses andlid massage, or eyelid cleaners may be recommended to help decreaseinflammation around the surface of the eyes.

Self Care

Steps to reduce symptoms of dry eyes include: Remembering to blinkregularly when reading or staring at a computer screen for long periodsof time. Increasing the level of humidity in the air at work and athome. Wearing sunglasses outdoors, particularly those with wrap aroundframe design, to reduce exposure to drying winds and sun. Usingnutritional supplements containing essential fatty acids may helpdecrease dry eye symptoms in some people. Avoiding becoming dehydratedby drinking plenty of water (8 to 10 glasses) each day.

Tear Stimulation by Direct Inducement of Reflex Tearing

One example of the present disclosure relates to stimulation ofinnervated areas proximal to the lacrimal system. More specifically, thenerve ending of interest (a branch of the nasociliary) is the anteriorethmoidal nerve 84 (as described in further detail below) that suppliessensory innervation to the mucous membrane of the nasal cavity and theinfratrochlear nerve. The nasociliary nerve is a branch of theophthalmic 96 division of trigeminal nerve. It is intermediate in sizeas compared to the other two branches of the ophthalmic division;frontal nerve 81 (larger) and lacrimal nerve 92 (smaller)(FIG. 2, asdiscussed in further detail below). Although stimulation of the nervesof the nasal cavity has been found in the prior art (e.g., Tsubota, K.(1998) “Tear Dynamics and Dry Eye,” Prog. Retin. Eye Res 17(4), 565-596;Ackermann, D. M. et al. “Nasal Stimulation Devices and Methods,” WIPOPCT Patent Publication Number WO/2014/172693, ApplicationPCT/US2014/034733, filed Apr. 18, 2014. (published 10/23/2014); andFujisawa, A. et al. (2002) “The Effect of Nasal Mucosal Stimulation onSchirmer Tests in Sjögren's Syndrome and Dry Eye Patients,” in LacrimalGland, Tear Film, and Dry Eye Syndromes 3 (Sullivan, D., et al., Eds.),pp 1221-1226, Springer US, each of which being incorporated herein byreference in its entireties), stimulation of the lacrimal system mucosaltissues and nerves therein have not.

The nasociliary nerve enters the orbit through the lower part of thesuperior orbital fissure, between the two heads of the lateral rectusmuscle. It then crosses above the optic nerve 98 (cranial nerve II), andruns forward along the upper margin of the medial rectus muscle.Finally, the nerve ends by dividing into the anterior ethmoidal nerve 84and the infratrochlear nerve.

The nasociliary nerve gives off a number of branches, as describedbelow:

Communicating branch to the ciliary ganglion: This communicating branchis actually composed of sensory fibers that arise in the eyeball. Theypass to the ciliary ganglion via the short ciliary nerves. Then theypass through the ciliary ganglion without interruption and join thenasociliary nerve via the communicating branch.

Long ciliary nerves: These are two or three small branches that arisefrom the nasociliary nerve while it crosses the optic nerve 98 in theorbital cavity. The long ciliary nerves pass forward alongside the shortciliary nerves and pierce the sclera of the eyeball. Then they continueforward between the sclera and the choroid to reach the iris. Thesenerves contain sympathetic fibers for the dilator pupillae muscle. Thusthey have a role in the pupillary reflex (light reflex).

Posterior ethmoidal nerve 85: This branch of the nasociliary nervesupplies the sphenoidal and ethmoidal air sinuses.

Infratrochlear nerve: This is a terminal branch of the nasociliary nervethat passes forward below the pulley (trochlea) of the superior obliquemuscle and innervates the skin of the medial part of the upper eyelid.It also innervates the adjacent part of the nose.

Anterior ethmoidal nerve 84: It is also a terminal branch of thenasociliary nerve. It passes through the anterior ethmoidal foramen toenter the anterior cranial fossa on the upper surface of the cribriformplate of ethmoid bone. The nerve then enters the nasal cavity through aslit like opening near the crista galli. It supplies the mucous membranehere. After supplying the mucous membrane, the anterior ethmoidal nerve84 appears on the face at the lower border of the nasal bone as theexternal nasal branch. Here it supplies the skin of the nose as far downas the tip.

Nerve Supply of the Excretory System

Sensory nerve supply to the lacrimal sac 16 is derived from theinfratrochlear nerve, which is the terminal branch of the nasociliarynerve, a branch of the ophthalmic division of the fifth cranial nerve(V¹). The lower portion of the nasolacrimal duct 18 receives sensationfrom the anterior superior alveolar branch of the maxillary division ofthe fifth cranial nerve (V²).

There may be a physiologic relationship between the innervation of thelacrimal gland 2 (lacrimal nerve 92) and the lacrimal sac 16(infratrochlear nerve), both being branches of the ophthalmic divisionof the fifth cranial nerve. This may explain why destruction of thelacrimal sac 16 leads to a decrease in tear secretion and why theepiphora of dacryocystitis may be caused in part by reflex irritationfrom the diseased sac 16 as well as from obstruction (see, e.g.,Whitnall, S. E. (1932) in The Anatomy of the Human Orbit and AccessoryOrgans of Vision 2nd ed., pp 208-252, Oxford University Press, London;and Iwamoto, T. and Jakobiec, F. (1982) “Lacrimal Glands,” in BiomedicalFoundations of Ophthalmology, Harper & Row, Philadelphia, each of whichis incorporated by reference herein in its entirety.)

The present disclosure involves an implant that resides within the tearexcretory pathway (puncta 10 to nasolacrimal duct 18) which possess thecapability to stimulate the mucosa of the lacrimal sac 16 and upperregion of the nasolacrimal duct 18 (innervated by infratrochlear nerve aterminal branch of V¹) and which leads to reflex tearing of the lacrimalgland 2 which also innervated by V¹. The stimulatory process is throughsonic, ultrasonic, mechanical, chemical, light or other means whichmight induce nerve response from the region of the lacrimal sac 16 andnasolacrimal duct 18. It should also be noted that the stimulatory forcemight extend past medial tissues to influence the septum of the nosewhich is also supplied by terminal branches of V¹ and which can alsocause reflex tearing. More specifically, the nerve ending of interest (abranch of the nasociliary) is the anterior ethmoidal nerve 84 whichsupplies sensory innervation to the mucous membrane of the nasal cavity.

According to aspects of the current disclosure, an implanted medicaldevice may be designed as a lacrimal system stimulator. It is a lacrimalsystem device with a bio-stimulus transducer and a faceplate and alsomay have an associated expandable component which may be implanted sothat the distal end may be expanded to conform to anatomical features ofthe lacrimal system and the proximal end faceplate is proximate to thetear film abutting the upper or lower punctum 10.

In order to eye treat dry eye, drugs are often required to beadministered to the eye. A conventional method of drug delivery is bytopical drop application to the eye's surface. Topical eye drops, thougheffective, can be inefficient. As one example, when an eye drop isinstilled in an eye, it often overfills the conjunctival sac (i.e., thepocket between the eye and the lids) causing a substantial portion ofthe drop to be lost due to overflow of the lid margin and spillage ontothe cheek. In addition, a large portion of the drop remaining on theocular surface can be washed away into and through a lacrimalcanaliculus, thereby diluting the concentration of the drug before itcan treat the eye. Moreover, topically applied drugs often have a peakocular effect for about two hours post-application, after whichadditional applications of the drugs should be, but are often not,administered to maintain the desired drug therapeutic benefit.

To compound ocular management difficulty, patients often do not usetheir eye drops as prescribed. This poor compliance can be due to, forexample, an initial stinging or burning sensation caused by the eye dropand experience by a patient. Instilling eye drops in one's own eye canbe difficult, in part because of the normal reflex to protect the eye.Therefore, one or more drops may miss the eye. Older patients may haveadditional problems instilling drops due to arthritis, unsteadiness, anddecreased vision. Pediatric and psychiatric populations posedifficulties as well.

Conditions of dry eye have been treated by blocking the tear flow fromthe eye into and through the lacrimal canaliculus 12. This has involvedclosing the canaliculus 12 by stitching the puncta 10 shut or by usingelectrical or laser cauterization to seal the puncta 10. Although suchprocedures can provide the desired result of blocking tear flow to treata dry eye, they are unfortunately not reversible without reconstructivesurgery.

In a field different from ocular management, control ofrespiration-related (e.g., allergies) diseases or disorders oftenrequires repetitive manual digestion or other intake of a medication,and as such, can be ineffective due to a lack of patient compliance ornon-localized drug delivery.

The Effect of Punctal Occlusion on Tear Production, Tear Clearance, andOcular Surface Sensation in Normal Subjects

Ocular irritation is a common complaint encountered by ophthalmologists.The mechanisms by which symptoms of irritation develop are stillunclear; however, most patients with ocular irritation have been foundto have a reduced tear break up time, indicative of tear filminstability. This may be the result in part of an aqueous teardeficiency, a lipid tear deficiency from meibomian gland disease, orother undefined causes. Recently, delayed tear clearance of fluoresceinhas been shown to correlate strongly with the severity of ocularirritation symptoms independent of aqueous tear production. Corneal andconjunctival sensitivity to touch were both found to decrease as tearclearance worsened. Furthermore, the concentration of theproinflammatory cytokine interleukin-la in tear fluid has been shown toincrease with progressive delay of tear clearance. These findingssuggest that delayed tear clearance may lead to chronic ocular surfaceinflammation that affects ocular surface tactile sensation and causesirritation symptoms. These findings suggest that treatment of ocularirritation should therefore be directed toward modulating the ocularsurface environment.

Although the most commonly used therapy for ocular irritation isinstillation of artificial tears, the improvement in symptoms is oftenshort-lived, because the tears evaporate and drain through the lacrimaldrainage system. Punctal occlusion is a simple procedure that can beused in an attempt to conserve naturally produced tears and also toprolong the contact time of artificial tears. The procedure has beenshown to decrease elevated tear osmolarity and rose bengal staining ofthe ocular surface, consistent with increased tear volume from retentionof aqueous tears. Punctal occlusion may have effects on tear physiologyin addition to simple mechanical blockage of the lacrimal outflow tract.Decreased tear turnover after punctal occlusion, which could result fromdecreased drainage or reduced production of aqueous tears, has beenpreviously reported (e.g., Yen, M. T. et al. (2001) “The Effect ofPunctal Occlusion on Tear Production, Tear Clearance, and Ocular SurfaceSensation in Normal Subjects,” Am. J. Ophthalmol. 131(3), 314-323,incorporated herein by reference in its entirty). Paradoxically,complete occlusion of the lacrimal drainage system often does not resultin frank epiphora. These findings suggest that punctal occlusion mayhave an active, although still undefined, role in tear and ocularsurface physiology. The purpose of the study was to evaluate the effectof temporary punctal occlusion on tear production, tear clearance, andocular surface sensation in normal subjects.

Temporary punctual occlusions with silicone plugs is a simple procedurethat can provide symptomatic relief to patients with ocular irritationsymptoms, especially those with severe aqueous tear deficiency. It isgenerally believed that the therapeutic mechanism of punctal occlusionis to increase the aqueous component of the preocular tear film byblocking the lacrimal outflow tract. The study clearly shows thatpunctal occlusion also has profound effects on ocular surface sensationand aqueous tear production. Indeed, the results of the Yen studysuggest that punctal occlusion influences the communication between theocular surface and lacrimal gland 12.

The results of the Yen study also indicate that one likely mechanism bywhich punctal occlusion affects tear secretion is by reducing ocularsurface sensation. We found that ocular surface sensation decreasedafter punctal occlusion. When only the lower puncta 10 were occluded,conjunctival sensation decreased significantly. However, no change incorneal sensation was noted in this group of subjects. One possibleexplanation for this finding may be that the Cochet-Bonnetanesthesiometer is not sensitive enough to measure subtle changes incorneal sensation. The cornea has a much greater sensory innervationcompared with the conjunctiva. Because the anesthesiometer has a scaleof only 0 to 6, it is plausible that any change in corneal sensation wasnot of sufficient magnitude to be measured with this instrument. Anotherpossible explanation for the lack of any measurable change in cornealsensation could be that occlusion of a single punctum 10 of an eye isnot adequate to produce a measurable decrease of corneal sensation. Whenboth puncta 10 of one eye were occluded, conjunctival and cornealsensations were noted to decrease initially. In these normal subjects,however, the ocular surface sensation began to return to preocclusionlevels by the end of the study. This finding suggests that anautoregulatory mechanism exists to normalize any changes in ocularsurface sensation. This mechanism may be defective in patients withocular irritation, because they have been noted to have decreasedcorneal sensitivity scores in multiple studies.

Consistent with the Yen findings of decreased ocular surface sensationis a concomitant decrease in sensory stimulated tear production,measured by the Schirmer 1 test, after punctal occlusion. In thesubjects with both puncta 10 of one eye occluded, tear production beganto stabilize toward the end of the observation period, similar to theirocular surface sensation. Several clinical reports have suggested thattear production and outflow of tears from the ocular surface are linked.Patients with acquired obstruction of the lacrimal drainage systemrarely have symptoms of epiphora. Lack of significant epiphora has alsobeen reported in patients with congenital absence of lacrimal puncta.Tomlinson and associates noted that a decrease in tear turnovercorrelated with a decrease in subjective symptoms of epiphora afterpunctal occlusion was performed. Aqueous tear production by the lacrimal2 is mainly driven by sensory neural stimulation from the trigeminalnerves innervating the ocular surface, adnexa, and nasal mucosa. The Yenfindings suggest that there may be receptors in the ocular surface,lacrimal outflow tract, or nasal mucosa that participate in a feedbackmechanism controlling tear production. In contrast to the Yen findingsin normal subjects, some dry eye patients have been reported to haveincreased Schirmer 1 test scores after punctal occlusion. Perhaps theunderlying cause of aqueous tear deficiency in some dry eye patients isexcessive negative feedback from the ocular surface or the tear drainageapparatus on lacrimal gland tear secretion. In these patients, punctalocclusion may reverse this process.

An interesting finding in the Yen study was that a decrease in tearproduction and ocular surface sensation was also measured in thecontralateral nonoccluded eye. Decreased tear production in thecontralateral eye has been reported in patients with unilateralneurotrophic keratitis. Crossed sensory stimulation of tear productionhas been postulated, with decreased trigeminal stimulation of one eyedecreasing sensory stimulated tear production bilaterally. Anotherpossibility is that a central control of tear production exists. A thirdpossibility is that decreased ocular surface sensation results in adecreased blink rate, which promotes an increase in tear filmevaporation. It would seem unusual for unilateral punctal occlusion toaffect the ocular surface sensation in the contralateral eye. The samepatients with unilateral neurotrophic keratitis were reported to havenear-normal corneal sensation scores in the unaffected eye. Perhaps thedecreased aqueous tear production in the contralateral eye that wasobserved after punctal occlusion leads to this decreased sensation. Thisis consistent with a correlation between tear production and ocularsurface sensation that was previously observed in patients with aqueoustear deficiency. Another possibility is that decreased tear clearanceleads to accumulation of such factors as opioid peptides or inflammatorycytokines in the tear film that affect the threshold of the sensorynerves on the ocular surface. Yet another possibility may be thatchanges in tear osmolality could act on the sensory nerves of the ocularsurface to decrease sensation. Similar to the occluded eye, ocularsurface sensation and tear production returned toward preocclusionlevels over time in the fellow eye. Again this suggests that regulationof tear production is a dynamic process and that autoregulatoryprocesses appear to exist that function to maintain tear homeostasis.

One implication of the Yen study may be that punctal occlusion may notbe appropriate therapy for all patients with ocular irritation. Patientscomplaining of ocular irritation are often given a generic diagnosis of“dry eye.” However, ocular irritation may have other underlying causes,such as meibomian gland dysfunction. The concentration of theproinflammatory cytokine interleukin-la has also been found to increasein the tear fluid as tear clearance decreases. Ocular irritation may becaused by chronic ocular surface inflammation in some cases, and punctalocclusion in these patients may worsen their symptoms by furtherdelaying their tear clearance and increasing the concentrations ofpathogenic factors in the tear fluid. Anti-inflammatory therapy may be abetter option for these patients. It is important to note that occlusionof only the inferior puncta in normal subjects did not significantlychange their tear clearance. Therefore, additional studies will berequired to assess the effects of therapeutic punctal occlusion inpatients with dry eye disease. As greater knowledge is gained about theregulation of the ocular surface/lacrimal gland integrated unit, newparadigms may emerge regarding which patients with dry eye disease maybenefit from punctal occlusion and which patients may have adverseconsequences.

Tear production from the lacrimal gland appears to be tied to a stimulusin the tear drainage system. If a plug to close off the tear drainagesystem is implanted, the mucosa there is no longer stimulated and thereis a reflex arc that may signal, trigger, or otherwise cause thelacrimal gland 2 to stop producing tears. This may mean that stimulatingthe mucosa, such as with the devices described herein, may induce themucosa to signal that tears were coming in and may lead to more tearproduction.

Detailed Description of Drawings

Described herein are devices, systems, and methods for treating one ormore conditions (such as DED) by providing stimulation to mucosa of thelacrimal sac 16 and upper region of the nasolacrimal duct 18. In oneexample, the device is implantable. Additional, more than one device maybe implantable per eye. In one example, two devices are implantable, oneeach through each punctum of an eye. In one example, two devices may bemagnetically linked after implantation. Further, the devices may includea stimulator body and a bio-stimulus transducer, where the bio-stimulustransducer includes one or more stimulus delivery zones. The stimulusdelivered by the stimulators described herein may in some variations beelectrical; in other variations, they may be mechanical, thermal,chemical, light-based, magnetic, or the like. When the devices andsystems are used to treat DED, the methods may include stimulatingmucosa of the lacrimal sac 16 and upper region of the nasolacrimal duct18 to increase tear production, reduce the symptoms of DED, or improveocular health.

In one example, the present disclosure includes an implant (e.g.,medical device, stimulator body) that resides in (e.g., is positionedwithin) the nasolacrimal system (puncta 10, canaliculi 12, lacrimal sac16) and outside of the nasal cavity. The device provides stimulus to thesurrounding mucosa through vibrational energy (sonic, ultrasonic) orthrough other stimuli such as high or low temperatures, mechanicalstretch and relaxation, and/or delivery of molecules that stimulate thesurrounding mucosa and adjacent structures. The stimulus then induces areflex arc through the nasociliary nerve to induce tearing from thelacrimal gland 2. The stimulus may be delivered on command throughremote sensor communication or programmed to deliver the stimulus on aspecific pre-programmed schedule. The device is removable in minimallyinvasive fashion. In another example, the stimulus is provided directlyto the caruncle 13 Error! Reference source not found. of the medialcanthus. In one arrangement, the device contains sensors thatcommunicate with both internal and external (remote) interfaces andsend/receive data. Further, the device could be for short-term (hours todays) to long-term use (months to years). In one example, the device maybe biodegradable or made from medical grade polymers and/or alloys thatare not biodegradable (e.g., silicone, acrylics, hydrogels, NiTi,titanium, steel, gold, etc.).

FIG. 1 illustrates a side-view of an eye 6 of a subject, including threelayers of naturally produced tears. For example, as shown in FIG. 1,naturally-produced tears are composed of an outer oily layer 6A, amiddle watery layer (e.g., the aqueous layer) 6B, and an inner mucuslayer 6C which spread across the surface of the eye 6 (e.g., the ocularsurface) whenever the subject blinks, thereby providing lubrication,washing away foreign matter, reducing the risk of infection, and keepingthe surface of the eye 6 smooth and clear.

FIG. 2 illustrates anatomical features of nerves and blood vesselsrelated to eye 6 and the lacrimal system of a subject. Such nerves andblood vessels include the dorsal nasal vessel 80, the frontal 81, themedial palpebral 82, the supraorbital 83, the anterior ethmoidal 84, theposterior ethmoidal 85, the muscular 88, the bulb of the eye 89, theciliary 90, the arteria centralis retinae 91, the lacrimal 92, thezygomatic branches 94, the ophthalmic 96, the internal carotid 97, thelacrimal gland 2, and the optic nerve 98.

FIG. 3 illustrates additional anatomical features related to thelacrimal system of the eye 6 of a subject. As shown, the lacrimal gland2 is positioned in the upper outer portion of the orbit of each eye 6.The lacrimal gland 2 includes the orbital (e.g., superior) portion 2Aand the palbebral (e.g., inferior) portion 2B. The lacrimal gland 2secretes the aqueous layer 6B of tears 4 which are delivered from thelacrimal gland 2 to the surface of the eye 6 via one or more channels orducts 8 of the lacrimal gland 2. Tears 4 drain from the eye 6, towards aplica semilunaris 11 and lacrimal caruncle 13 via the nasolacrimaldrainage system, which includes two puncta 10 located on a lacrimalpapilla (e.g., superior lacrimal papilla 10A or inferior lacrimalpapilla 10B). Each puncta 10 includes a minute orifice or opening influid communication with canaliculi 12. The canaliculi 12 converge anddrain into the lacrimal sac 16, which in turn, is in fluid communicationwith the nasolacrimal duct 18.

In order to induce tear production, one or more devices may bepositioned within the nasolacrimal drainage system to prompt orstimulate the lacrimal gland 2. For example, FIG. 4 illustrates anexemplary medical device 100, e.g., stimulating device, according toaspects of the present disclosure. The device 100 may include astimulator body 112 extending between a proximal end 104 and a distalend 103 and may have a length between about 1 mm and about 30 mm. Insome arrangements, for example, stimulator body 112 have a lengthbetween about 25 mm and about 30 mm such that stimulator body 112 mayextend through the puncta 10, through the canaliculus 12, and into thelacrimal sac 16 and/or the nasolacrimal duct 18. In other arrangements,however, stimulator body 112 may have a length between about 1 mm andabout 10 mm. A diameter of stimulator body 112 may be between about 250μm and about 1.5 mm. Stimulator body 112 may be tapered (e.g., comprisea varied diameter or dimension along its length) so as to narrow in thedirection extending from proximal end 104 to distal end 103. In someexemplary arrangements, a distal-most end of stimulator body 112 may beabout 500 μm to facilitate implantation, as will be described in furtherdetail below.

The device 100 may include a power source 110 and a control subsystem108 with a distal end bio-stimulus transducer 113 in electroniccommunication the control subsystem 108. In some aspects, the powersource 110 may include a battery, and the control subsystem 108 mayinclude at least logic and communication circuits. An enlarged faceplate105 may be located at the proximal end 104 of the device 100 and mayinclude at least one sensor 106 and at least one antenna 107 inelectronic communication with the control subsystem 108. The simulatorbody 112 and the faceplate 105 may be formed (e.g., extruded, molded,etc.) as a one-piece continuous structure. Alternatively, in somearrangements, the stimulator body 112 may be joined to the faceplate 105via any appropriate manner such as, for example, adhesive(s), mechanicalfaster(s), or welding. In one example, the device 100 may furtherinclude an isolation coupling 111.

FIG. 5 illustrates an additional exemplary medical device 200, e.g.,stimulating device, according to aspects of the present disclosure.Similar to device 100, the device 200 may include a stimulator body 112comprising a power source 110 and a control subsystem 108 with a distalend bio-stimulus transducer 113 in electronic communication the controlsubsystem 108. The power source 110 may include a battery and thecontrol subsystem 108 may include at least logic and communicationcircuits. Similar to device 100, device 200 may include a proximal end104 faceplate 105. The faceplate 105 may include at least one sensor 106and at least one antenna 107 in electronic communication with thecontrol subsystem 108. In one example, the device 200 further includesan isolation coupling 111. The stimulator body 112 may further include acentral drainage lumen 220. In one aspect, at least the distal end 103of the device 200 may flexible. Additionally, the stimulator body 112may further include an expandable component 114. The expandablecomponent 114 may be connected to a faceplate port 117 via a lumen 118.Additionally, in some arrangements, the stimulator body 200 may furtherinclude a therapeutic agent reservoir 115 which may be connected to afaceplate port 117 via a lumen 119. In some aspects, the stimulator body112 may further include multiple zones comprising electrodes 116. In onearrangement, the stimulator body 112 further includes at least onedistal end magnetic component 221.

FIGS. 6-9 illustrate further exemplary stimulators according to aspectsof the current disclosure. For example, as shown in FIG. 6, an exemplarystimulator device may include a body 20 extending between a proximal end22 and a distal end 24. The body 20 may have a length between about 1 mmand about 30 mm. In some arrangements, for example, the body 20 may havea length between about 25 mm and about 30 mm such that the body 20 mayextend through the puncta 10, through the canaliculus 12, and into thelacrimal sac 16 and/or the nasolacrimal duct 18. In other arrangements,however, the body 20 may have a length between about 1 mm and about 10mm. A diameter of the body 20 may be between about 250 μm and about 1.5mm. As shown, the body 20 may be tapered (e.g., comprise a varieddiameter or dimension along its length) so as to narrow in the directionextending from the proximal end 22 to the distal end 24. In someexemplary arrangements, a distal-most end of the body 20 may be about500 μm to facilitate implantation, as will be described in furtherdetail below.

The proximal end 22 may be coupled to or monolithically formed with afaceplate 26. For example, in some arrangements, the body 20 and thefaceplate 26 may be formed (e.g., extruded, molded, etc.) as a one-piececontinuous structure. Alternatively, in some arrangements, the body 20may be joined to the faceplate 26 via any appropriate manner such as,for example, adhesive(s), mechanical faster(s), or welding. As shown inFIG. 6, the faceplate 26 may be enlarged relative to body 20. That is, aradial dimension (e.g., diameter) of the faceplate 26 may be larger thana radial dimension (e.g., diameter) of the body 20. In such a manner,the faceplate 26 may include a flange, collar, and/or projection whichmay be received adjacent (e.g., abutting) the puncta 10 of thenasolacrimal drainage system, as will be described in further detailbelow. Thus, the faceplate 26 also may function to plug or otherwiseblock a portion of the puncta 10 to prevent drainage of tears throughpuncta the 10. In some arrangements, the faceplate 26 may be rounded,curved, or non-planar, as shown in FIG. 6. As such, the entirety of thestimulator device may be atraumatic. The faceplate 26 may optionallyinclude a coating or be impregnated with a photo-active material (notshown). Such photo-active materials may include, e.g., fluorescein whichmay be activated (e.g., excited) upon the application of an appropriateenergy source such as, e.g., sunlight and/or ultraviolet light of aspecific wavelength (e.g., blue light). Upon activation, thephoto-active material may emit light within the visible spectrum. Assuch, a user may verify the proper placement of the faceplate 26 in oradjacent to the puncta 10 by observing the light emitted by thephoto-active material.

The body 20 and the faceplate 26 may include any one or morebiologically compatible materials such as, for example, medical-gradestainless steel, nitinol, titanium, etc.; and/or polymers, such aspolyurethane, silicone, Polylactic acid (PLA), Polylactic-co-glycolicacid (PLGA), Polyglycolide (PGA), and/or Polycaprolactone (PCL). In somearrangements, an antimicrobial or other therapeutic agent (not shown)can be coated on, or impregnated in, at least a portion of the outersurface of the body 20 and/or the faceplate 26 to, e.g., preventmicrobial growth. Optionally, the body 20 and/or the faceplate 26 may bemicropatterned (e.g., manufactured) with grooves, recesses, or othersurface irregularities (not shown). Such grooves may have a depth ofbetween about 1 μm and about 50 μm and may decrease the overall surfacearea in contact with surrounding tissues. Such grooves also may preventbacterial adherence to an outer surface of the body 20 and/or thefaceplate 26. Additionally or alternatively, a coating of TitaniumDioxide, Silver, or other such bacteriostatic or bactericidal materialsmay be applied to or impregnated within body 20 and/or faceplate 26. Asshown in FIG. 6, the body 20 may include one or more cut-outs, openings,or windows 28. For example, the body 20 may include a single window 28,as shown in FIG. 6. Alternatively, however, the body 20 may include apair of windows 28 on opposing sides of the body 20. That is, thewindows 28 may be diametrically opposed and equidistantly spaced about acircumference of the body 20. The windows 28 also may be laterally,vertically, and/or radially offset from one another. In otherarrangements, the body 20 may include any number of windows 28positioned about the circumference of body 20. For example, the body 20may include between about 1 and about 10 windows 28. The windows 28 maybe equally spaced about a circumference of the body 20. Alternatively,the windows 28 may be unequally spaced about the circumference of thebody 20. Each window 28 may be located at a common axial positionbetween the proximal end 22 and the distal end 24 of the body 20.Alternatively, the windows 28 may be located at varying axial locationsbetween the proximal end 22 and the distal end 24 of the body 20. Forexample, the body 20 may define a first “ring” or grouping of windows 28arranged about the circumference of the body 20 at a first axiallocation and a second, or more “rings” or groupings of windows 28arranged about the circumference of the body 20 at a second or moreaxial locations of the body 20.

As shown in FIG. 6, the window 28 may be rectangular. However, thewindow 28 may be square, circular, oval, triangular, polygonal, orirregular shaped without departing from the scope of this disclosure.Additionally, one or more windows 28 may have a different size and/orshape relative to another window 28. For example, each window 28 mayhave a varied size, shape, and/or orientation relative to any otherwindow 28. The window 28 may include an opening in the body 20 so as toexpose one or more stimulus delivery mechanisms such as, for example, aconductor 30. For example, the conductor 30 may include a conductivewire (e.g., a 30-guage wire). The conductor 30 also may include anysuitable electrode (e.g., plate electrode). The conductor 30 may be, forexample, comprised at least in part of one or more of copper, silver,aluminum, other such metals. Depending on the particular materialselected, impedance of the conductor(s) 30 may be between about 800 Ωand about 2,000 Ω. For example, impedance of the conductor(s) 30 may beabout 1,500 Ω.

A pair of conductors 30 (only one visible in FIG. 6) may extend from theface plate 26 towards the distal end 24 of the body 20. In use, portionsof the conductors 30 within the windows 28 may directly contact or touchtissue within the canaliculi 12. That is, the window(s) 28 is designedto expose the conductor(s) 30 to adjacent tissue (e.g., nerves, mucosa,etc.) for excitation or stimulation of such tissue. In somearrangements, a pair of conductors 30 may be arranged in a bipolarfashion. That is, a first conductor 30 may be configured as a first pole(e.g., anode) of a bipolar arrangement while a second conductor 30 maybe configured as a second pole (e.g., cathode) of a bipolar arrangement.Alternatively, each conductor 30 itself may comprise a bipolarconductor. In such an arrangement, a return path (not shown) may bearranged along body 20 in the form of a reference electrode. Further, insome arrangements, the conductor(s) 30 may be arranged forsingle-channel or multi-channel stimulation of tissue. In sucharrangements, constant current may be applied so that impedance at theload is not changing the amount of current that is reaching the tissueof interest during stimulation.

The faceplate 26 may include an inductive coil 32. The coil 32 may beoperably coupled to the conductor(s) 30 and may wirelessly communicatewith an external stimulation device. In some arrangements, the coil 32may be a radiofrequency (RF) coil which may be configured to receiveand/or transmit RF signals. For example, the coil 32 may be configuredto facilitate communication of data and/or energy between theconductor(s) 30 and an external source. For example, in somearrangements, the coil 32 may be a portion of a control subsystem 34which may optionally include a memory (not shown). The control subsystem34 may be positioned on or within the faceplate 26. Alternatively,however, the control subsystem 34 may be positioned along or within body20. The control subsystem 34 may be configured to communicate wirelessly(e.g., via Wi-Fi, Bluetooth, or the like) with an external device 36(e.g., an external programmer, base station, laptop, computer, mobiledevice, phone, tablet, wearable computer (e.g., optical head-mounteddisplays such as Google Glass™) or the like). The external device 36 mayinductively transfer energy to the coil 32. In some arrangements, thecontrol subsystem 34 may be solely passive. That is, the controlsubsystem 34 may not be configured for active control of the stimulatordevice, but rather, only to execute commands received from the externaldevice 36 or the like. Optionally, the control subsystem 34 may includea power source (e.g., battery) to supply power to the control subsystem34. In some arrangements, the external device 36 may be positioned nearor adjacent the implanted stimulator device including the coil 32, and auser may actuate the external device 36 to inductively deliver energy tothe coil 32, and consequently, the conductor(s) 30.

The external device 36 may be used by the user (e.g., the subjectthemselves or a medical professional) to power the stimulator device onor off, start or stop stimulus, change an intensity of stimulus, changea duration of stimulus, change a stimulus pattern, or the like. In onearrangement, the external device 36 may be able to activate ordeactivate different functions, and/or may be able to change differentparameters, based on their manner of operation (e.g., pressing a buttonbriefly, pressing a button for a prolonged period of time, pressing abutton with a particular pattern of pressing actions, rotating a dial bydifferent angles or different speeds). Each of the one or more operatingmechanisms may be any suitable structure, such as but not limited to abutton, slider, lever, touch pad, knob, or deformable/squeezable portionof the housing, and a stimulator may include any combination ofdifferent operating mechanisms.

Additionally or alternatively, in some variations external device 36 mayinclude a display, which may be configured to convey information to auser via text and/or images. Additionally or alternatively, the externaldevice 36 may include a speaker or buzzer configured to produce one ormore speech prompts or other sounds. Additionally or alternatively, theexternal device 36 may be configured to vibrate. When external device 36is configured to vibrate, the duration and/or repetition of thevibration may convey information to the user.

Optionally, the stimulator device may further include one or moresensors 40. As shown in FIG. 6, the sensor 40 may be positioned on thefaceplate 26. However, the sensor 40 may be positioned along the body 20without departing from the scope of this disclosure. The sensor 40 maybe configured for sensing biochemical properties of tears 4 in the eye6, placement of, and/or operation of the stimulator device. For example,the sensor 40 may sense a degree of conductivity, may be a molecularsensor, and/or may be a biological sensor. For instance, in somearrangements, the sensor 40 may evaluate or sense the degree of moistureadjacent the sensor 40, thereby evaluating whether additional tears 4should be induced via application of stimulation by the conductor(s) 30.In some arrangements, the sensor 40 may communicate with the externaldevice 36 (and/or an additional external device). In such arrangements,the proximity of the sensor 40, and therefore, the faceplate 26 or thebody 20 relative to the external device 36, may be readily ascertainedby a user to verify the proper placement of the faceplate 26 and/or thebody 20 within the puncta 10 or the canaliculus 12.

Upon delivery of a signal from the external device 36, upon detecting apre- determined condition via the sensor 40 (e.g., an indication ofinsufficient tears), or upon the expiration of a pre-determined periodof time, energy may be delivered to tissue via the electrode(s) 30. Forexample, energy having a pulse rate of between about 1 Hz and about 200Hz, with a pulse duration of between about 10 μsec to about 500 μsec,and having a pulse amplitude between about 0.1 mA to about 5 mA may beapplied via electrode(s) 30. In some exemplary arrangements, energy maybe delivered in the form of an active bi-phasic, symmetric, chargedbalance waveform with an interpulse delay of 100 μsec. A total treatmenttime may be between about 5 seconds and about 20 seconds.

In use, the stimulator device may be positioned inside the nasolacrimaldrainage system through the puncta 10 and into a canaliculus 12. In allarrangements disclosed herein, however, the stimulator device ispositioned externally of the nasal cavity. That is, while portions ofthe stimulator device may be received within the lacrimal sac 16 and thenasolacrimal duct 18, no portion of the disclosed stimulator devices isreceived at any time within the nasal cavity of a subject during use. Inorder to induce tears 4, the conductor(s) 30 may be energized to providestimulus to the surrounding tissue in the canaliculus 12 through one ormore of electrical excitement of tissue, a piezoelectric element forvibrational excitement (e.g., sonic or ultrasonic), and/or aheating/cooling element for thermal excitement. Further examples ofstimulus may include one or more of a light-generating devices (notshown), magnetic-field generating devices (not shown), pulsed fluid(e.g., air) delivery devices (not shown), and/or chemical agents (notshown). The stimulus then induces a reflex arc through the tissue of thecanaliculus 12. For example, the stimulus applied via the conductor(s)30 may excite one or more of the nasociliary nerve, the supratrochlearnerve, and the infratrochlear nerve to induce tearing from the lacrimalgland 2. In one arrangement, the stimulator device could be arranged forshort term (hours to days) or long term use (months to years). In somearrangements, the stimulator device may be biodegradable or made frommedical grade polymers and/or alloys that are not biodegradable(silicone, acrylics, hydrogels, NiTi, titanium, steel, gold, etc.).

FIG. 7 illustrates a further exemplary arrangement of a stimulatordevice for stimulation of tissue. The stimulator device of FIG. 7 may besimilar to that of FIG. 6, and as such, may include a pair of conductors30 operably coupled to a coil 32 positioned in the faceplate 26. Asshown in FIG. 7, the conductors 30 may extend along radially outersurfaces of the body 20. While not shown in FIG. 7, one or more windowssimilar to the window 28 shown in FIG. 6 may be arranged or embeddedalong portions of the body 20 so as to expose the conductors 30 totissue. In other arrangements, the conductors 30 may extend along anexterior circumferential surface of body 20 and may be flush with anexterior surface of the body 20. In one arrangement, the conductors 30may be embedded within the thickness of body 20. In addition, thestimulator device of FIG. 7 may include a lumen 50 extending throughfaceplate 26 and body 20. The lumen 50 may be configured to drain tears4 therethrough from the proximal end 22 towards the distal end 24. Inyet a further arrangement, as shown in FIG. 8, the faceplate 26 may beomitted. Instead, the coil 32 may be positioned on, embedded within, orarranged about the body 20. In addition, the control subsystem 34 andany sensors 40 may be positioned on or embedded within the body 20. Insuch arrangements, the entirety of the body 20 may be received within acanaliculus 12 of the nasolacrimal drainage system.

In a further arrangement, as shown in FIG. 9, the body 20 may becomprised of a braid or mesh 52. The mesh 52 may comprise a network ofstruts 52 a forming a plurality of closed cells 54. Although not shown,in some arrangements, the porosity of the mesh 52 may vary along thelength of the mesh 52. Optionally, the mesh 52 may be configured toexpand to varying dimensions (e.g., diameters) along the length of thebody 20. That is, portions of the mesh 52 may expand to a greater extentthan other portions of the mesh 52 so as to form a series of peaks andvalleys along the body 20. As such, the portions of the mesh 52expanding to a greater extent (not shown) may firmly contact tissue,while the portions of the mesh 52 expanding to a lesser extent (notshown) may not be in contact with the tissue. As such, an overallpressure exerted by the body 20 on the tissue may be reduced orminimized.

The mesh 52 may comprise any one or more appropriate biocompatiblematerials, such as, for example, Nitinol or polymer. Optionally, themesh 52 may be comprised of a conductive material. In such arrangements,separate conductors 30 may not be necessary. Rather, stimulation may bedelivered to tissue of the canaliculus 12 through the conductive mesh52. In some arrangements, the mesh 52 may be self-expanding. That is,upon insertion of the body 20 including mesh 52 within a canaliculus 12,the mesh 52 may expand so as to maintain contact between the conductors30 and tissue within the canaliculus 12. In other arrangements, the mesh52 may not be self-expanding. That is, upon deployment within thecanaliculus 12, an expansion device (e.g., a balloon) may be insertedwithin the lumen 50 and expanded (e.g., inflated) so as to expand themesh 52. In either arrangement, the mesh 52 may urge, push, or otherwisemaintain the conductors 30 in contact with tissue so as to increase theefficacy of stimulation. For example, as shown in FIG. 10, thestimulator device of FIG. 9 may be inserted into a canaliculus 12 of thenasolacrimal drainage system. While only a single stimulator device isillustrated within the nasolacrimal drainage system, multiple stimulatordevices may be arranged therein. For example, a first stimulator devicemay be positioned within a canaliculus 12 while a second stimulatordevice may be positioned within a second canaliculus 12 of thenasolacrimal drainage system. Additionally or alternatively, multiplestimulator devices may be positioned within the same or a commoncanaliculus 12 of the nasolacrimal drainage system. Although not shown,the stimulator devices of FIG. 8 and FIG. 9 may further include afaceplate 26 as shown in FIGS. 6 and 7.

FIG. 11 illustrates an exploded view of a still further arrangement inwhich the body 20 includes a retention portion 60. The retention portion60 may be selectively expandable so as to expand to facilitate retentionof body 20 within the canaliculus 12. The retention portion 60 mayinclude a balloon or other such expandable member which, upon insertionof a fluid (e.g., air, saline, hydrogel, etc.) through a delivery lumen(not shown), may expand as shown in FIG. 11, to lodge, catch, orotherwise fix the body 20 in place within the canaliculus 12.Optionally, the retention portion 60 may be comprised of aself-expanding material. That is, upon exposure of the retention portion60 to body heat within canaliculus 12, the retention portion 60 mayexpand. FIG. 12 illustrates an exploded view of yet an additionalarrangement in which the body 20 may include a spring or coil. In somearrangements, the body 20 may be an extension of the coil 32, or may bea discrete member joined to the coil 32. As shown, the conductor 30 mayextend along the length of the coil of the body 20. Additionally, insome arrangements, the coil of the body 20 may itself be conductive,thus, eliminating the need for a separate conductor 30.

In a further arrangement, as shown in FIG. 13, a plurality of stimulatordevices may be arranged in the nasolacrimal drainage system. Forexample, two stimulator devices may be arranged in a first canaliculus12, while an additional two stimulator devices may be arranged in asecond canaliculus 12. A first stimulator device 70 within eachcanaliculus 12 may include a faceplate 26 positioned to abut the puncta10 of each canaliculus 12. A second stimulator device 72 within eachcanaliculus 12 may not include faceplate 26. As such, each secondstimulator device 72 may be received entirely within a canaliculus 12.As shown in FIG. 13, the first and second stimulator devices 70, 72 mayhave varied arrangements. For example, first stimulator devices 70 maybe similar in construction and function to the stimulator deviceillustrated in FIG. 7, while second stimulator devices 72 may be similarin construction and function to the stimulator device illustrated inFIG. 9. However, such an arrangement is merely exemplary. In alternativearrangements, each of the first and second stimulator devices 70 and 72may be the same or different than every other stimulator device.

As shown in FIG. 13, each of first and second stimulator devices 70 and72 may include a magnet member 74. For example, the first stimulatordevice 70 in a first canaliculus 12, may include a magnetic member 74having a pole orientation opposite that of a magnetic member 74 in thesecond stimulator device 72 in the first canaliculus 12. Similarly, thefirst stimulator device 70 in a second canaliculus 12, may include amagnetic member 74 having a pole orientation opposite that of a magneticmember 74 in the second stimulator device 72 in the second canaliculus12. That is, pairs of stimulator devices within a common canaliculus 12may be attracted to one another to maintain a relative positioning ofthe first stimulator device 70 relative to the second stimulator device72. Alternatively, the first stimulator device 70 in a first canaliculus12, may include a magnetic member 74 having a pole orientation similarto that of a magnetic member 74 in the second stimulator device 72 inthe first canaliculus 12. Similarly, the first stimulator device 70 in asecond canaliculus 12, may include a magnetic member 74 having a poleorientation similar to that of a magnetic member 74 in the secondstimulator device 72 in the second canaliculus 12. That is, pairs ofstimulator devices within a common canaliculus 12 may be opposed fromone another to maintain a relative spacing of the first stimulatordevice 70 relative to the second stimulator device 72. In addition,either or both of the first stimulation device 70 or the secondstimulation device 72 in the first canaliculus 12 may be coupled (e.g.,magnetically) with either or both of the first stimulation device 70 orthe second stimulation device 72 of the second canaliculus 12. In such amanner, two stimulation devices 70 or 72 can be inserted at same timeand may couple or connect and anchor each other in place.

In order to insert any of the above disclosed stimulator devices of FIG.4, 5, 6-9, 11, or 12, a user may gather the following items: A punctaldilator, any of the above disclosed stimulator devices, and a suitableforceps. Any appropriate punctal dilator may be used such as, forexample, a reusable autoclavable stainless steel dilator. Next, the usermay apply a drop of topical anesthetic to the puncta 10 of the subjectto numb or dull the sensitivity in the area. Next, the subject may bearranged behind a slit lamp and if necessary, a user may dilate thepuncta 10 of the subject. Then, the user may grasp any of theabove-described stimulator devices (e.g., via the body 20) with theforceps and insert the distal end 24 into the puncta 10. The user maycontinue insertion of the stimulator device until either (1) theentirety of the stimulator device is positioned through the puncta 10and in the canaliculus 12, or (2) until the faceplate 26 (if applicable)abuts the puncta 10. Next, the user may visualize the implantedstimulator device via the slit lamp to ensure proper orientation. Ifnecessary, the user may additionally apply gentle downward pressure onthe implanted stimulator device until the faceplate 26 (if applicable)abuts or is flush against the puncta 10. The user then may repeat thisprocess as necessary to insert all required stimulator devices withinthe nasolacrimal drainage system of a subject. Additionally, in the caseof the stimulator device of FIG. 9, if mesh 52 is not a self-expandingmesh, the user may deliver an inflation mechanism (e.g., a balloon) intolumen 50 to expand mesh 52.

In arrangements where the stimulator device includes the lumen 50 (orthe lumen 222), an introducer (not shown) may be extended through thelumen 50 (or the lumen 222) towards the distal end 24 (or distal end103) until an end of the introducer abuts or otherwise engages a portionof the distal end 24 (or the distal end 103), and/or is coupled to thedistal end 24 (or the distal end 103). The introducer then may bemanipulated so as to stretch or otherwise tension the body 20 (or thebody 112) such that a diameter of the body 20 (or the body 112) may bereduced temporarily from a resting state diameter to a reduced caliberdiameter. After stretching, the body 20 (or body 112) may be insertedthrough the puncta 10 and the canaliculus 12. Upon insertion, theinsertion device may be uncoupled or removed from the lumen 50 (or thelumen 222) such that body 20 (or body 112) may reassume or expand to itsresting state diameter. Such an arrangement may facilitate enhancingcontact between the body 20 (or the body 112) and surrounding tissue, aswell as enhancing the body 20 (or the body 112) retention within thecanaliculus 12. In this arrangement, a user may not be required todilate the puncta 10.

Further, in some arrangements, a device may be used to test the efficacyof the stimulation dosage prior to implantation of one of theabove-described stimulation devices. As such, a probe (not shown) may beoperably connected to an energy source (either wirelessly or via a wiredconnection) and may be positioned in the canaliculus 12. The powersource then may be calibrated until a desired tearing response is notedby the subject and/or the user. Such a desired tearing response may bedetermined either subjectively or through objective measurementsincluding, for example, Schirmer testing or optical coherence tomographyimaging of the tear lake.

While previous therapeutic devices are known (see, e.g., U.S. Pat. Nos.5,713,833; 7,146,209; 8,996,137; and U.S. Patent Application PublicationNo. 2013/0006326, all of which are incorporated herein by references intheir entireties) the devices disclosed herein may exhibit a number ofbenefits including, for example: 1) Upon implantation or insertion, noportion of the disclosed devices herein enter the nasal cavity or touchthe septum; 2) Upon implantation or insertion, the devices disclosedherein may be located completely within the tear drainage system whichempties into the nasal cavity but is distinct from the nasal cavity; 3)The disclosed devices may include a proximal end faceplate that may beeasily accessible for device removal if needed; 4) The disclosed devicesmay not require interaction with the subject and can be inserted onetime and act for a short or long duration; 5) The disclosed system canbe used to analyze the tear film at the level of the faceplate andprovide real time feedback for the tear film environment; 6) The systemmay avoid contact with the vascular nasal cavity and is therefore lesslikely to cause bleeding, inflammation, and/or discomfort; and 7) Thesystem may treat dry eyes through two separate mechanisms which includeblocking outflow of tears from the ocular surface into the tear drainagesystem and providing stimulus at the level of the nasolacrimal mucosa toproduce more tears.

Further discussion of various components of the disclosed examples willnow follow below.

User Interface

In instances where the stimulators described herein include a userinterface, the user interface may include one or more operatingmechanisms, which may allow the user to control one or more functions ofthe stimulator. For example, the operating mechanisms may allow the userto power the device on or off, start or stop the stimulus, change theintensity of the stimulus, change the duration of the stimulus, changethe stimulus pattern, or the like. In one example, the operatingmechanisms may be able to activate or deactivate different functions,and/or may be able to change different parameters, based on their mannerof operation (e.g., pressing a button briefly, pressing a button for aprolonged period, pressing a button with a particular pattern ofpressing actions, rotating a dial by different angles or differentspeeds). Each of the one or more operating mechanisms may be anysuitable structure, such as but not limited to a button, slider, lever,touch pad, knob, or deformable/squeezable portion of the housing, and astimulator may include any combination of different operatingmechanisms.

Additionally or alternatively, in some variations the stimulator bodymay include a display, which may be configured to convey information toa user via text and/or images. Additionally or alternatively, thestimulator body may include a speaker or buzzer configured to produceone or more speech prompts or other sounds. Additionally oralternatively, the stimulator body may be configured to vibrate. Whenthe stimulator body is configured to vibrate, the duration and/orrepetition of the vibration may convey information to the user. Itshould be appreciated that when the stimulator is configured to delivera mechanical stimulus (e.g., vibration), as described in more detailbelow, vibration and/or noise caused by the mechanical stimulus deliverymay be used to convey information to the user.

As previously mentioned, a plurality of vibrating elements can beemployed according to the instant disclosure. When a plurality ofpiezoelectric vibrating elements are employed, they should be alignedsuch that the vibrational waves that they emit do not compress eachother or diminish the effects of the waves that one or the others emit.In cases where the vibrating elements are stacked (i.e., contacting eachother) those skilled in the art will recognize that the poles of thevibrating elements should be aligned such that positive poles arecontacting each other and negative poles are at opposite ends of thestack. On the other hand, if multiple vibrating elements are notstacked, but are spaced from one another, they are preferably spacedfrom each other at locations on, for example, a shaft where the energyof the waves which they emit is at a minimum. These locations areprimarily based upon the wavelength of the waves created by thevibrating elements.

It should be appreciated that while the user interfaces described aboveare located on the stimulator bodies, in other variations, all of aportion of the user interface of the stimulator may be located on thebio-stimulus transducer. Additionally or alternatively, all or a portionof the user interface may be located on a separate unit, which may bephysically or wirelessly attached to the stimulator. For example, invariations where the stimulator is configured to connect to a computeror mobile device (e.g., cellular telephone, tablet, wearable computer(e.g., optical head-mounted displays such as Google Glass™), or thelike, as will be discussed in more detail below), the mobile device mayact as a user interface. For example, the mobile device may act as adisplay to convey information to the user or may allow the user tocontrol or program the device.

Control Subsystem

Generally, the control subsystem may be configured to control a stimulusto be delivered to a subject via the bio-stimulus transducer. Thecontrol subsystem may be contained within the housing the stimulator.The control subsystem may be connected to the operating mechanisms ofthe stimulator (e.g., the buttons), which may allow the controlsubsystem to receive input from a user. The control subsystem also maybe connected to mechanisms configured to provide feedback or otherwiseconvey information to a user.

Additionally or alternatively, the control subsystem may include acommunications subsystem. The communication subsystem may be configuredto facilitate communication of data and/or energy between the stimulatorand an external source. For example, in some variations thecommunications subsystem may be configured to allow the stimulator tocommunicate wirelessly (e.g., via Wi-Fi, Bluetooth, or the like) with anexternal device (e.g., an external programmer, base station, laptop orother computer, mobile device such as a mobile phone, tablet, wearablecomputer (e.g., optical head-mounted displays such as Google Glass™) orthe like), and may include an antenna, coil, or the like. Additionallyor alternatively, the communication subsystem may be configured tocommunicate with an external device (e.g., a flash drive, a laptop orother computer, a mobile device such as a mobile phone, palm pilot, ortablet, or the like) via a wired transmission line. In these variations,the stimulator may include one or more ports (e.g., a USB port),connectors and/or cables configured to physically connect the stimulatorto an external device, such that data and/or energy may be transmittedbetween the stimulator and the external device.

Power Source

The stimulator may include a power source. The power source may be anysuitable power supply capable of powering one or more functions of thestimulator, such as one or more batteries, capacitors, or the like. Inone example, the power source may be rechargeable. In one example, therechargeable power source may be recharged wirelessly.

Electrodes

When the stimulators described herein are configured to deliver anelectrical stimulus, at least one of the bio-stimulus transducers mayinclude one or more electrodes configured to deliver a stimulus totissue. In some other variations, for example, an electrode may beellipsoid or spherical, ovoid, or the like. In yet other variations, theelectrodes may include an array of electrodes. In one example, having anarray of electrodes may allow a stimulus to be delivered to tissue evenif one or more of the electrodes in the array fails, and/or mayfacilitate unilateral stimulation with a lacrimal system bio-stimulustransducer. When an electrical stimulus is delivered through theelectrodes, the stimulation energy may be directed toward the mucosa.This may allow for selective activation of nerves in the mucosa, whileminimizing activation of nerves toward collateral areas. The electrodemay have any suitable length, such as between about 1 mm and about 10mm, between about 3 mm and about 7 mm, about 5 mm, or more than about 10mm.

The electrode(s) described herein may be made from one or moreconductive materials. In one example, the electrodes may comprise metals(e.g., stainless steel, titanium, tantalum, platinum orplatinum-iridium, other alloys thereof, or the like), conductiveceramics (e.g., titanium nitride), liquids, gels, or the like. In oneexample, the electrode may comprise one or more materials configured topromote electrical contact between electrodes of the bio-stimulustransducer and tissue (i.e., all of an electrodes or a portion of theelectrode, such as a covering). In some instances, the impedanceprovided by tissue may be at least partially dependent on the presenceor absence of fluid-like materials (e.g., mucous) in the lacrimalsystem. The material(s) may help to minimize the impact of subjecttissue impedance by providing a wet interface between the electrode andtissue, which may act to normalize the impedance experienced by theelectrodes. This may in turn normalize the output and sensationexperienced by the user.

While the bio-stimulus transducers are described in some instancesherein with respect to delivery of an electrical stimulus, it should beappreciated that the stimulators described herein may be configured todeliver other types of stimuli, including mechanical, chemical, or otherforms of stimulation. In variations in which the stimulators areconfigured to deliver a mechanical stimulus, the lacrimal systembio-stimulus transducers may be configured to deliver vibrational energyto mucosa of the lacrimal sac and upper region of the nasolacrimal duct.In variations where a stimulator may include one or more bio-stimulustransducers configured to be inserted at least partially into a lacrimalsystem (such as described herein), the bio-stimulus transducers may beconfigured to vibrate relative to tissue. In variations where astimulator is implanted in a nasal or sinus cavity, one or more portionsof the stimulator may be configured to vibrate. In one example, thevibration may be generated using one or more magnetic componentspositioned externally of the body. In these variations, mechanicalenergy may be used to activate mechanical receptors in afferent neurons.

Additionally or alternatively, the lacrimal system bio-stimulustransducers may be configured to deliver ultrasonic energy to tissue. Inthese variations, the lacrimal system bio-stimulus transducers (andstimulator bodies) may be configured to have similar physical propertiesas described herein, although the lacrimal system bio-stimulustransducers need not include electrodes. Instead, the lacrimal systembio-stimulus transducers or the stimulator body may include vibratingmotors in variations configured to vibrate all or a portion of thelacrimal system stimulator, or may include one or more ultrasoundtransducers configured to deliver ultrasonic energy. In one example, theultrasound transducers may be located in place of the electrodesdescribed herein.

In some other variations, the stimulators described herein may beconfigured to deliver thermal, light-based, and/or magnetic stimuli. Inone example, stimulators may be configured to deliver one or more pulsesof air to tissue via the lacrimal system bio-stimulus transducers, whichmay stimulate tissue. The pulses of air may be generated via a source ofcompressed air, or the like. In one example, the gas may be warmed orcooled (e.g., mechanically or via one or more thermally-activatedfibers). In other variations, the lacrimal system bio-stimulustransducers may be heated or cooled to provide thermal stimulation totissue. Additionally or alternatively, the stimulator may include one ormore light-generating or magnetic field-generating elements, which maybe used to stimulate mucosa of the lacrimal sac and upper region of thenasolacrimal duct via the lacrimal system bio-stimulus transducers.

In yet other variations, the bio-stimulus transducers may be configuredto deliver one or more chemical agents to mucosa of the lacrimal sac andupper region of the nasolacrimal duct. The chemical agent may be one ormore drugs, such as a histamine receptor agonist, nicotinic agonist, orthe like. In other variations, the chemical agent may contain one ormore irritants, such as ammonia, benzene, nitrous oxide, capsaicin(e.g., propanethial S-oxide), mustard oil, horseradish, crystallinesilica, or the like. The lacrimal system bio-stimulus transducers may inthese instances include delivery ports for delivering one or morechemical agents, and may additionally include lumens connecting thedelivery ports to one or more reservoirs located in the base member ofthe stimulation bio-stimulus transducer and/or in the stimulator body.

Electrical Connection

Generally, when the stimulators described herein are configured todeliver an electrical stimulus, the electrodes of the stimulator may beelectrically connected to the stimulator circuitry, such that thestimulator may generate a stimulus and deliver it to tissue via one ormore of the electrodes. Accordingly, the stimulators described hereinmay include one or more electrical connections configured toelectrically connect the electrode via a lead to a portion of thestimulator body (e.g., a stimulation subsystem housed in the stimulatorbody). In variations in which the bio-stimulus transducer and stimulatorbody are indirectly connected, the indirect connection (e.g., a cable,cord, or the like) may serve as the electrical connection between thestimulator circuitry and the electrodes. In variations in which thebio-stimulus transducer and the stimulator body are directly connected,the stimulator body and bio-stimulus transducer may include conductiveelements configured to electrically connect the electrodes of thebio-stimulus transducer to the stimulator circuitry when the body andbio-stimulus transducer are connected.

Disposable Design

In one example, some portion or all of the stimulator may be disposable.In variations where the stimulator body is permanently attached to thebio-stimulus transducer, the entire stimulator may be disposable. Inother variations, one or more portions of the stimulator may bereusable. For example, in variations where the bio-stimulus transduceris releasably connected to the stimulator body, the stimulator body maybe reusable, and the bio-stimulus transducer may be disposable. As such,the bio-stimulus transducer may be periodically replaced, such as willbe described in more detail below. In yet other variations, a portion ofthe bio-stimulus transducer section may be disposable (e.g., thebio-stimulus transducer may include disposable sections) and may beperiodically replaced. In one example, the stimulators described hereinmay include features that encourage or require a user to replace astimulator or stimulator components after a certain period or on aregular basis in order to main proper hygiene.

Additionally or alternatively, in some variations the stimulator may beconfigured to alert the user and/or enter an inoperable state when aused bio-stimulus transducer is attached to the stimulator body. Thestimulator may alert the user in any suitable manner, and mayadditionally or alternatively be configured to instruct the user toreplace the bio-stimulus transducer, as described herein. In thesevariations, the stimulators may include a mechanism for determiningwhether the attached bio-stimulus transducer is new (i.e., whether thebio-stimulus transducer has been previously attached to a stimulatorbody or not). In one example, the mechanism for determining whether thebio-stimulus transducer is new may include a fuse. In one example, thefuse may temporarily short circuit the stimulator circuitry while thebio-stimulus transducer is being connected to the stimulator body.

Additionally or alternatively, the base station may be configured towirelessly transmit or receive data from the stimulator. In variationswhere data may be transmitted between the stimulator and the basestation, the base station may be configured to provide programminginstructions to the stimulator. The base station may be configured to beattached to an external computing device, to transfer data downloadedfrom the stimulator and/or receive programming instructions to beprovided to the stimulator. In variations where the base station mayinclude a port (such as a USB port), the port may be used to attach thebase station to an external computing device.

External Device Connection

In some variations the stimulators described herein may be configured toconnect to an external device, such as a mobile device (e.g., a cellulartelephone, a tablet, a wearable computer (e.g., optical head-mounteddisplays such as Google Glass™), or the like), a computer, or the like.The stimulators may be configured to connect to an external devicethrough any suitable connection method. In some variations theconnection method may be wireless (e.g., via Wi-Fi, Bluetooth, or thelike), and the stimulator may include an antenna or the like. In oneexample, the device may be programmed via a program application or “app”on an external device. In one example, the device may be operated in areal time operation with a connection to an external device by way ofcommunication through the device antenna. Additionally or alternatively,the connection method may be via a wired transmission line. In thesevariations, the stimulator may include one or more ports (e.g., a USBport), connectors and/or cables configured to physically connect thestimulator to an external device. In one example, the stimulators mayuse a wireless or wired connection to connect to the internet, via whichthey may be connected to an external device. In these variations, thedevice may be at a distant location (e.g., at the manufacturer, at aphysician's office, or the like).

In instances in which the stimulators are configured to connect to anexternal device, the device may be configured to perform one or moreoperations associated with the stimulator. For example, in variationswhere the stimulator is configured to collect data (e.g., one or moresubject parameters, stimulation timing or parameters, stimulatordiagnostic information, such as described in more detail herein) andstore that data in a memory unit of the stimulator, connection of thestimulator to the device may allow for transfer of data stored in thestimulator's memory unit to the device. Specifically, the device andstimulator may be programmed such that upon connection of the device andthe stimulator, the device may download the recorded data stored in thestimulator's memory. In one example, once data has been transferred fromthe stimulator to the device, the stimulator may be configured to deletethis data from the stimulator memory. Because the amount of memoryavailable in the device may be greater than that in the stimulator, thistransfer may increase the data that may be accumulated for a subject.

In addition to or instead of transferring data stored in the stimulatormemory, a device may be configured to collect and store real-time datafrom the stimulator when the two are connected. In one example, thestimulator also may be configured to store this data in the stimulatormemory. In some instances, the device may be configured to transmit data(e.g., via internet connection, cellular data network, or the like) fromthe device to an external location (e.g., to a database where the datamay be analyzed, to a physician's office to allow the physician tomonitor the data and, in some instances, provide feedback).

In one example, the device may be configured to solicit input from auser. For example, if the stimulator is used to provide stimulationwhile attached to a device, the device may be configured to solicit theuser to input data regarding the subject's experience (e.g., a subject'slevel of comfort/discomfort, status of subject's symptoms). In oneexample, the device may be configured to present data (and/or analysisof the data) to a user. For example, the device may be configured todisplay information regarding the frequency of stimulation, the averageduration of stimulation, a graph of subject comfort levels over time, orthe like. In one example, the device may be configured to share the dataor analysis of the data with the manufacturer, clinicians, friends, orothers.

Implantable Stimulators

In some variations of the stimulation systems described here, thestimulation system may include a stimulator configured to be implanted,either permanently or temporarily, in a subject. It should beappreciated that the implantable stimulators need not be surgicallyimplanted. In some of these instances, the implantable stimulator may beconfigured such that the stimulator may be inserted and/or removed by auser. In others of these instances, the implantable stimulator may beconfigured to be inserted and/or removed by a medical professional. Inother instances, the stimulator may be configured to be implanted in orotherwise attached to tissue within a nasal or sinus cavity.

In still other variations, the stimulation systems described herein mayinclude a stimulator that is configured to be implanted within orbeneath mucosal tissue. The stimulator may be implanted in a nasal orsinus cavity, and may be placed within the mucosa, beneath the mucosa,between mucosa and bone and/or cartilage, within the cartilage, or thelike. Generally, the stimulator may include a stimulator body and one ormore electrodes, and may include any of the stimulators described inU.S. Patent Application Publication No. 2013/0006326 A1, filed on Apr.6, 2012, and titled “Stimulation devices and methods,” which waspreviously incorporated by reference in its entirety.

Device Insertion

While not limiting the current disclosure, one method of insertion ofthe device would be to introduce the unexpanded device on the punctalside in an insertion method similar to the introduction of a Crawfordtube. In one example, the expandable distal end of the device isenvisioned to fit through the punctum and canaliculus wherein thereservoir of the device would reside in the lacrimal sac allowing forpotential expansion to conform to anatomical features. In one example,the proximal end faceplate rests upon the punctum. In one example, alubricant is coupled with the system to allow for smoother atraumaticinsertion. While not limiting the device, it is envisioned that thedevice would conform the standard anatomical size variations. In oneexample, the device could be used for subjects of various sizes and ageranges. In one example, the device may not be appropriate in certainsubjects, including, but not limited to subjects with trauma to thenasolacrimal system, subjects with chronic nasal inflammation, ordacryocystitis. Dacryocystitis is an inflammation of the lacrimal sac,frequently caused by nasolacrimal duct obstruction or infection. In oneexample, the device functions and serves for at least two months orgreater than sixty days. In the particular cases of treating dye eye,the device therapy would last at least two months.

Stimulation Methods

Generally, the stimulators and stimulation systems described herein maybe configured to stimulate mucosa of the lacrimal sac and upper regionof the nasolacrimal duct. In one example, the stimulation may be used tocause tear production by a user. Generally, a stimulator (such asdescribed above) may be configured to stimulate one or more nasal orsinus afferents which may activate a lacrimation response via anasolacrimal reflex. In some instances, this may include stimulating oneor more branches of the trigeminal nerve or trigeminal nerve afferents.In some of these instances, this may include stimulating the ophthalmic96 branch of the trigeminal nerve. This stimulation may be used to treatvarious forms of dry eye, including (but not limited to), chronic dryeye, episodic dry eye, seasonal dry eye, aqueous deficient dry eye, orevaporative dry eye.

In some instances, the stimulation may be used as a prophylactic measureto treat users which may be at an increased risk of developing dry eye,such as subjects who will undergo or who have undergone ocular surgerysuch as refractive vision correction and/or cataract surgery. In otherinstances, the stimulators may be used to treat ocular allergies. Forexample, an increase in tear production may flush out allergens andother inflammatory mediators from the eyes. In some instances, thestimulation delivered by the stimulators described herein may beconfigured to cause habituation of the neural pathways that areactivated during an allergic response (e.g., by delivering a stimulationsignal continuously over an extended period of time). This may result inreflex habituation which may suppress the response that a user wouldnormally have to allergens.

Location

When an implantable stimulator is used to provide stimulation, theimplantable stimulator may be positioned in a nasal or sinus cavity (ormultiple nasal or sinus cavities). When a stimulator is used to providestimulation, one or more lacrimal system bio-stimulus transducers of thestimulator may be activated in the lacrimal system of a user, and astimulation signal (such as described above) may be delivered to themucosal tissue.

A portion of the lacrimal system bio-stimulus transducer(s) may bepositioned and/or manipulated to be placed in contact with any suitabletissue. (In variations in which the stimulators are configured todeliver an electrical stimulus, the stimulators may be positioned and/ormanipulated to position electrodes into contact with any suitabletissue.) For example, the lacrimal system bio-stimulus transducer(s) maybe placed in contact with the tear drainage system or nasolacrimalmucosa or the like. When the stimulators are used to produce a tearingresponse as discussed herein, it may be desirable to position a portionof the bio-stimulus transducers (e.g., an electrode) in contact with thelacrimal system mucosa. In some instances, the targeted area may includetissue innervated by the infratrochlear nerve. In some instances, thetargeted area of the lacrimal system mucosa may be between the punctumand the nasolacrimal duct. In one example, it may be desirable to placea portion of the bio-stimulus transducer(s) (e.g., an electrode) betweenabout 0.5 mm and about 30 mm into the tear drainage system of thesubject. As described herein, it may in some instances be desirable todirect the bio-stimulus transducer such that a portion (e.g., theelectrodes) is directed toward the lacrimal sac and duct. Avoidingstimulation of the septal nerves and surrounding nerves is desirable soas to reduce negative side effects that may occur from inadvertentstimulation of the olfactory area.

Electrical Stimulus

In one example, the stimulation may be delivered unilaterally (e.g., ina single nostril). For example, in variations where a stimulator mayinclude a single bio-stimulus transducer, the bio-stimulus transducermay be placed in a through one punctum and into the lacrimal system, andstimulation may be delivered to the lacrimal system via the bio-stimulustransducer. It should be appreciated that in some of these variations inwhich the stimulus is electrical, an electrode or other return electrodemay be affixed to or otherwise be placed in contact an anatomical areaexternal to the lacrimal system a return electrode. In one example, suchexternal connection to the electrode may be used in a testing phase ofthe device, post implantation. In some variations where a stimulator mayinclude two or more bio-stimulus transducers, each of the bio-stimulustransducers may be placed in a first punctum per eye, and some or all ofthe bio-stimulus transducers may be used to deliver stimulation tomucosal tissue. In other variations where a stimulator may include twoor more bio-stimulus transducers, at least one bio-stimulus transducermay be positioned in a first punctum per eye, and at least onebio-stimulus transducer may be positioned in the second punctum per eye.In some examples, each eye may have two devices implanted into eachlacrimal system. In one example, each punctum of the eye may contain oneimplanted medical device. In variations in which the stimulus iselectrical, some or all of the bio-stimulus transducers in each lacrimalsystem may be used to deliver unilateral electrical stimulation to eachlacrimal system (e.g., the bio-stimulus transducer(s) in each lacrimalsystem may remain independently inactive).

In one example, the stimulators may be used to provide bilateralstimulation of the lacrimal system mucosal tissue. In these variations,at least one stimulator device including a bio-stimulus transducer maybe positioned in a first lacrimal system and at least one stimulatordevice including a bio-stimulus transducer may be positioned in a secondlacrimal system. In these variations, when the stimulus is electrical,electrical stimulation may be delivered between the bio-stimulustransducer in the first lacrimal system and the bio-stimulus transducerof the second lacrimal system, which may cause current to flow betweenthe two devices.

Electrical Stimulus: Waveforms

When the stimulus is electrical, the electrical stimulus delivered bythe stimulators described herein may include a waveform or waveforms,which may be tailored for specific treatment regimens and/or specificsubjects. The waveforms may be pulse-based or continuous. It should beappreciated that the waveforms described herein may be delivered via abipolar configuration or a monopolar configuration. When the stimulatoris configured to deliver a continuous waveform, the waveform may be asinusoidal, quasi-sinusoidal, square-wave, saw tooth/ramped, ortriangular waveform, truncated-versions thereof (e.g., where thewaveform plateaus when a certain amplitude is reached), or the like.Generally, the frequency and peak-to-peak amplitude of the waveforms maybe constant, but in some variations the stimulator may be configured tovary the frequency and/or amplitude of the waveform. This variation mayoccur according to a pre-determined plan, or may be configured to occurrandomly within given parameters. For example, in some variations thecontinuous waveform may be configured such that the peak-to-peakamplitude of the waveform varies over time (e.g., according to asinusoidal function having a beat frequency). In some instances varyingthe amplitude and/or frequency of a stimulation waveform over time, orpulsing the stimulus on and off (e.g., 1 second on/1 second off, 5seconds on/5 seconds off), may help reduce subject habituation (in whichthe subject response to the stimulation decreases during stimulation).Additionally or alternatively, ramping the amplitude of the stimulationwaveform at the beginning of stimulation may increase comfort.

When the stimulator is configured to create a pulse-based electricalwaveform, the pulses may be any suitable pulses (e.g., a square pulse, ahaversine pulse, or the like). The pulses delivered by these waveformsmay by biphasic, alternating monophasic, or monophasic, or the like.When a pulse is biphasic, the pulse may include a pair of single phaseportions having opposite polarities (e.g., a first phase and acharge-balancing phase having an opposite polarity of the first phase).In one example, it may be desirable to configure the biphasic pulse tobe charge-balanced, so that the net charge delivered by the biphasicpulse is approximately zero. In one example, a biphasic pulse may besymmetric, such that the first phase and the charge-balancing phase havethe same pulse width and amplitude. Having a symmetric biphasic pulsemay allow the same type of stimulus to be delivered to each lacrimalsystem. The pulses of a first phase may stimulate a first side of thenose (while providing a charge-balancing phase to a second side of thenose), while the pulses of the opposite phase may stimulate the secondside of the nose (while providing a charge-balancing phase to the firstside of the nose). In other variations, a biphasic pulse may beasymmetric, where the amplitude and/or pulse width of the first pulsemay differ from that of the charge-balancing phase. Additionally, eachphase of the biphasic pulse may be either voltage-controlled orcurrent-controlled. In one example, both the first phase and thecharge-balancing phase of the biphasic pulse may be current-controlled.In other variations, both the first phase and the charge-balancing phaseof the biphasic pulse may be voltage-controlled. In still othervariations, the first phase of the biphasic pulse may becurrent-controlled, and the second phase of the biphasic pulse may bevoltage-controlled, or vice-versa.

In variations where the waveform may include a biphasic pulse, thebiphasic pulse may have any suitable frequency, pulse widths, andamplitudes. For example, in instances where the stimulators describedherein are used to treat dry eye or otherwise produce a tearing responseby stimulating mucosa of the lacrimal sac and upper region of thenasolacrimal duct, the stimulator may be configured to generate abiphasic pulse waveform at a frequency between about 0.1 Hz and about200 Hz. In one example, the frequency is preferably between about 10 Hzand about 60 Hz. In one example, the frequency is preferably betweenabout 25 Hz and about 35 Hz. In one example, the frequency is preferablybetween about 50 Hz and about 90 Hz. In one example, the frequency ispreferably between about 65 Hz and about 75 Hz. In other variations, thefrequency is preferably between about 130 Hz and about 170 Hz. In oneexample, the frequency is preferably between about 145 Hz and about 155Hz. In one example, high frequencies, such as those between about 145 Hzand about 155 Hz may be too high for each pulse to stimulate/activatethe target nerves. As a result, the stimulation may be interpreted bythe patient to have an element of randomness, which in turn may help toreduce subject habituation.

Similarly, for the treatment of dry eye, the when the stimulus iselectrical and the first phase of the biphasic pulse iscurrent-controlled, the first phase may preferably have an amplitudebetween about 10 μA and 100 mA. In one example, the amplitude may bepreferably between about 0.1 mA and about 10 mA. When the first phase ofthe biphasic pulse is voltage-controlled, the first phase may preferablyhave an amplitude between about 10 mV and about 100 V. Additionally, thefirst phase may preferably have a pulse width between about 1 μs andabout 10 ms. In one example, the pulse width may preferably be betweenabout 10 μs and about 100 μs. In other variations, the pulse width maypreferably be between about 100 μs and about 1 ms.

When an electrical pulse waveform is an alternating monophasic pulsedwaveform, each pulse delivered by the stimulator may have a singlephase, and successive pulses may have alternating polarities. Generally,the alternating monophasic pulses are delivered in pairs at a givenfrequency (such as one or more of the frequencies listed above, such asbetween 30 Hz and 50 Hz), and may have an inter-pulse interval betweenthe first and second pulse of the pair (e.g., about 100 us, between 50us and 150 us or the like). Each pulse may be current-controlled orvoltage-controlled, and consecutive pulses need not be bothcurrent-controlled or both voltage-controlled. In some variations wherethe pulse waveform is charged-balanced, the waveform may include e apassive charge-balancing phase after delivery of a pair of monophasicpulses, which may allow the waveform to compensate for chargedifferences between the pulses.

When a stimulator configured to deliver an electrical stimulus ispositioned to place an electrode on either side of the nasal septum,alternating monophasic pulses may promote bilateral stimulation ofmucosa of the lacrimal sac and upper region of the nasolacrimal duct.The pulses of a first phase may stimulate a first side of the nose(while providing a charge-balancing phase to a second side of the nose),while the pulses of the opposite phase may stimulate the second side ofthe nose (while providing a charge-balancing phase to the first side ofthe nose), since nerves may respond differently to anodic and cathodicpulses. The inter-pulse interval may give time for the stimulationprovided by a first phase pulse to activate/polarize the target nervesprior to be reversed by an opposite phase pulse.

When a stimulator is configured to deliver a pulse-based waveform, thestimulation amplitude, pulse width, and frequency may be the same frompulse to pulse, or may vary over time. For example, In one example, theamplitude of the pulses may vary over time. In one example, theamplitude of pulses may vary according to a sinusoidal profile. In oneexample, the stimulation waveform may be a modulated high frequencysignal (e.g., sinusoidal), which may be modulated at a beat frequency ofthe ranges described above. In such variations, the carrier frequencymay be between about 100 Hz and about 100 kHz. In other variations, theamplitude of pulses may increase (linearly, exponentially, etc.) from aminimum value to a maximum value, drop to the minimum value, and repeatas necessary. In one example, the user may be able to control thestimulus during its delivery. After the device has been portioned withbio-stimulus transducer(s) (e.g., the electrode or electrodes) incontact with the mucosa of the lacrimal sac and upper region of thenasolacrimal duct, the user may increase the intensity of the stimulusvia a remote operation system. It may be desirable for the patient toincrease the intensity of the stimulus until the stimulus causesparesthesia (e.g., tingling, tickling, prickling). As such, the patientmay be able to self-determine the proper stimulation intensity andself-adjust the stimulus to a level effective to achieve the desiredresult (e.g., tear production). It may be desirable for the user toincrease the intensity of the stimulus slowly in order to minimizediscomfort.

In some instances, it may be desirable to configure the stimulationwaveform to minimize side effects. In some instances, it may bedesirable to promote stimulation of larger-diameter nerves (e.g.,afferent fibers of the trigeminal nerve), which may promote atherapeutic effect, while reducing the stimulation of smaller nerves(e.g., a-delta fibers, c fibers, sympathetic and parasympatheticfibers), which may result in pain, discomfort, or mucus production. Oneway to avoid these fibers is to directly stimulate the mucosa in thelacrimal sac while avoiding the nasal cavity and septum. Generally, forsmaller pulse-widths, the activation threshold for larger-diameternerves may be lower than the activation threshold for the smaller nervefibers. Conversely, for larger pulse-widths, the activation thresholdfor larger-diameter nerves may be higher than the activation thresholdfor the smaller nerve fibers. Accordingly, in some instances, it may bedesirable to select a pulse width that preferably actuations thelarger-diameter nerves. In one example, the pulse width may be between30 μs and about 70 μs, or may be between about 30 μs and about 150 μs.

It should be appreciated that the electrical stimulation devices andsystems described herein may be used for one or more diagnosticfunctions, to modulate blood flow (e.g., to treat headaches), to promotehealing, or the like. Additionally, the stimulation systems, devices,and methods described are herein are intended for use with human users,it should be appreciated that they may be modified for veterinary use.

Chemical Stimulus

In one example, one or more chemical agents may be delivered to mucosaof the lacrimal sac and upper region of the nasolacrimal duct to treatone or more conditions. For example, In one example, one or morechemical agents may be used to treat dry eye or otherwise promote atear-producing response. In one example, the chemical agent may beconfigured to promote trigeminal nerve activation. The chemical agentmay be delivered in any suitable manner. In one example, the chemicalagent may be delivered via a stimulator as described herein. In othervariations, the chemical agent may be delivered via one or more eyedrops (which may drain through the device into the lacrimal system). Thechemical agent may include one or more of the agents described above.

Mechanical, Thermal, Light-Base, and Magnetic Stimulus

As mentioned above, in some variations the stimulation systems describedherein may be used to provide mechanical, thermal, light-based and/ormagnetic stimulation. In one example, a stimulator may be used todeliver vibrational energy to mucosa of the lacrimal sac and upperregion of the nasolacrimal duct. In variations where a stimulator mayinclude one or more bio-stimulus transducers configured to be inserted alacrimal system (such as the electrical stimulators described herein)and made to vibrate. In variations where a stimulator is implanted in alacrimal system, one or more portions of the stimulator may vibratewhile implanted. In one example, the vibration may be generated usingone or more magnetic components positioned externally of the body.

Additionally or alternatively, ultrasonic energy may be delivered totissue by a stimulator including one or more ultrasound transducers. Invariations in which stimulators are configured to deliver one or morepulses of air to tissue, one or more pulses of air may be delivered tostimulate tissue. The pulses of air may be generated via a source ofcompressed air, or the like. In one example, the gas may be warmed orcooled (e.g., mechanically or via one or more thermally-activatedfibers). In other variations, one or more portions of a stimulator maybe heated or cooled to provide thermal stimulation to tissue. Invariations where a stimulator may include one or more bio-stimulustransducers configured to be implanted with a lacrimal system, thestimulator may controllably heat or cool the bio-stimulus transducer.Additionally or alternatively, a stimulator may use one or morelight-generating or magnetic field-generating elements to stimulatemucosa of the lacrimal sac and upper region of the nasolacrimal duct.

Treatment Regimens

The stimulation methods described herein may be delivered according toone or more treatment regimens to treat a condition. For example, totreat dry eye, stimulation may be delivered to a subject as-neededand/or according to a pre-determined regimen. In some instances, a usermay use one of the stimulation devices described herein to provide around of stimulation when the user experiences symptoms of dry eye. Around of stimulation may have any suitable duration (e.g., between 0.1second and 10 minutes).

In other instances, the devices may be used to provide stimulation on ascheduled basis. For example, in some variations the stimulation devicesdescribed herein may be used to provide a round of stimulation at leastonce daily, at least once weekly, or the like. In one example, thestimulation devices may be used to deliver multiple rounds ofstimulation each day (e.g., at least two treatments daily, at leastthree treatments daily, at least four treatments daily, at least fivetreatments daily, at least six treatments daily, at least seventreatments daily, at least eight treatments daily, between two and tentimes daily, between four and eight times daily, or the like). In oneexample, the stimulation may be delivered at certain times of day. Inother variations, the stimulation may be delivered at any time duringthe day as desired or determined by the user. When the device is used toprovide stimulation on a scheduled basis, in some variations each roundof stimulation may be the same length (e.g., about 30 seconds, about 1minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5minutes, about 10 minutes, or longer than 10 minutes). In othervariations, some rounds of stimulation may have different predeterminedlengths. In yet other variations, the user may choose the length of theround of stimulation. In one example, the user may be given a minimumstimulation time (e.g., about 5 seconds, about 10 seconds, about 30seconds, about 1 minute, about 2 minutes, about 3 minutes, about 5minutes, or the like) and/or a maximum stimulation time (e.g., about 1minute, about 2 minutes, about 3 minutes, about 5 minutes, about 10minutes, about 20 minutes, or the like). In some instances, the deliveryschedule or stimulation parameters may be changed based on the time ofday (e.g., daytime use vs. nighttime use). In one example, thestimulator may include (e.g., as part of a control subsystem) one ormore counters and intelligence (e.g., a microcontroller, programmablelogic (e.g., a field-programmable gate array), or application-specificintegrated circuit (ASIC)). A counter may count oscillator pulses untila certain number have passed, at which point stimulation may beactivated. Additionally or alternatively, a counter may measure theduration of stimulation and the intelligence may control the stimulationlength. In some examples, the stimulation may follow a custom activationpattern programmed by an external device via wireless communication.

In some examples, the stimulation may be delivered on a continuousbasis. When an implantable stimulator is used to deliver stimulationnon-continuously as discussed herein, the implantable stimulator may beconfigured to deliver stimulation automatically or may be configured todeliver stimulation on command. For example, in some variations thestimulator may be configured to deliver stimulation on a pre-programmedbasis (e.g., according to a treatment regimen as discussed herein). Inother variations, the stimulator may include one or more sensors, andmay be configured to deliver stimulation upon detecting a pre-determinedcondition with the one or more sensors. For example, In one example, astimulator may include a wetness sensor, and may be configured todeliver stimulation when the wetness sensor registers a certain drycondition in a nasal or sinus cavity. When an implanted stimulator isactivated by a user, an external controller may be used (e.g., via awireless signal such as Bluetooth, near-field RF, far-field RF, or thelike) to activate the implanted stimulator.

Treatment Effects

In one example, the treatment regimens described herein may be used totreat dry eye. Current treatment options for dry eye are limited, andthey generally provide limited symptom relief or improvement in ocularhealth. In contrast to current treatment options, the treatment regimensusing the stimulators described herein may provide rapid and markedrelief and improvement in ocular health, as measured by numerousindicators, including tear production, patient symptoms, and corneal andconjunctival staining. Both the speed and magnitude of relief andimprovement in ocular health that may be achieved is surprising giventhe much slower and more limited ability to treat dry eye with existingtreatments. In one example, the treatment regimens of providing thestimuli described herein may cause periodic or regular activation of thenasolacrimal reflex, which may in turn treat dry eye and/or improveocular health. Periodic or regular activation of the nasolacrimal reflexmay improve ocular health by several mechanisms of action. For example,the activation of the nasolacrimal reflex may cause tearing, which inturn may deliver growth factors contained in the tears to the ocularsurface. These growth factors include epidermal growth factor (EGF). EGFis a polypeptide that stimulates the growth of various tissues,including the cornea, conjunctiva, and goblet cells. In patients withdry eye, the cornea may become damaged due to desiccation andinflammation; EGF may thus play a role in stimulating the healingprocess for the cornea. Periodic or regular activation of thenasolacrimal reflex also may improve ocular health by increasing restingtear production, which may promote chronic hydration of the ocularsurface, as well as by causing periodic or regular significant increasesin tear production during activation. Activation of the nasolacrimalreflex also may improve ocular health by causing vasodilation, which mayin turn promote ocular health.

In some examples, an antimicrobial coating can be disposed on, orimpregnated in, at least a portion of the outer surface of the implantbody to further prevent microbial growth on the implant body. In anexample, the antimicrobial coating can include an agent selected fromthe group including 2-bromo-2-nitropropane-1,3-diol,5-bromo-5-nitro-1,3-dioxane, 7-ethyl bicyclooxazolidine, benzalkoniumchloride, benzethonium chloride, benzoic acid, benzyl alcohol, boricacid, bronopol, cetylpyridinium chloride, chlorhexidine digluconate,chloroacetamide, chlorobutanol, chloromethyl isothiazolinone and methylisothiazoline, dimethoxane, dimethyl oxazolidine, dimethyl hydroxymethylpyrazole, chloroxylenol, dehydroacetic acid, diazolidinyl urea,dichlorobenzyl alcohol, DMDM hydantoin, ethyl alcohol, formaldehyde,glutaraldehyde, hexachlorophene, hexetidine, hexamethylenetramine,imidazolidinyl urea, iodopropynyl butylcarbamate, isothiazolinones,methenammonium chloride, methyldibromo glutaronitrile, MDM hydantoin,minocycline, ortho phenylphenol, p-chloro-m-cresol, parabens(butylparaben, ethylparaben, methylparaben), phenethyl alcohol,phenoxyethanol, piroctane olamine, polyaminopropyl biguanide,polymethoxy bicyclic oxazolidine, polyoxymethylene, polyquaternium-42,potassium benzoate, potassium sorbate, propionic acid, quaternium-15,rifampin, salicylic acid, selenium disulfide, sodium borate, sodiumiodate, sodium hydroxymethylglycinate, sodium propionate, sodiumpyrithione, sorbic acid, thimerosal, triclosan, triclocarban,undecylenic acid, zinc phenosulfonate, and zinc pyrithione. In anexample, the antimicrobial coating can include a material selected fromthe group comprising silver lactate, silver phosphate, silver citrate,silver acetate, silver benzoate, silver chloride, silver iodide, silveriodate, silver nitrate, silver sulfadiazine, silver palmitate or one ormore mixtures thereof. In an example, the antimicrobial coating caninclude at least one of an antibiotic or an antiseptic. For instance,the antimicrobial coating can include a temporary anesthetic lasting, onaverage, between a few hours and a day. In still other examples, theantimicrobial coating can include a drug use to treat an underlyingdisease, such as a bolus for immediate effect.

Each of the arrangements disclosed herein may include one or more of thefeatures described in connection with any of the other disclosedarrangements. The foregoing description is exemplary and explanatoryonly and are not restrictive of the features. As used herein, the terms“comprises,” “comprising,” or other variations thereof, are intended tocover a non-exclusive inclusion such that a process, method, article, orapparatus that comprises a list of elements does not include only thoseelements, but may include other elements not expressly listed orinherent to such a process, method, article, or apparatus. Additionally,the term “exemplary” is used herein in the sense of “example,” ratherthan “ideal.”

While principles of the present disclosure are described herein withreference to illustrative arrangements for particular applications, itshould be understood that the disclosure is not limited thereto. Thosehaving ordinary skill in the art and access to the teachings providedherein will recognize additional modifications, applications, aspects,and substitution of equivalents all fall within the scope of thearrangements described herein. Accordingly, the disclosure is not to beconsidered as limited by the foregoing description.

1-30 (canceled)
 31. A device for inducing production of tears,comprising: a body extending from a proximal end to a distal end,wherein the body is comprised of a braid or mesh and is configured forinsertion through a punctum of a subject; a stimulus delivery mechanismpositioned between the proximal end and the distal end; and a faceplateadjacent the proximal end of the body; wherein the faceplate abuts, andis located external to, the punctum when the body is inserted throughthe punctum.
 32. The device of claim 31, wherein the braid or mesh iscomprised of one or more biocompatible materials.
 33. The device ofclaim 32, wherein the one or more biocompatible materials is Nitinol ora polymer.
 34. The device of claim 31, wherein the faceplate includes apower receptor at least partially disposed therein or thereon.
 35. Thedevice of claim 31, wherein the mesh is self-expanding.
 36. The deviceof claim 35, wherein the mesh self-expands into conformity with aportion of a nasolacrimal drainage system of the subject after insertionof the body through the punctum.
 37. The device of claim 31, wherein themesh is not self-expanding.
 38. The device of claim 31, wherein separateportions of the mesh are conductive so that delivery of a stimulationsignal to the stimulus delivery device causes stimulation to bedelivered through the separate portions of the mesh to a tissue of anasolacrimal drainage system of the subject.
 39. The device of claim 38,wherein the body includes a lumen extending therethrough.
 40. A methodfor inducing tears, comprising: inserting a stimulation delivery devicethrough a punctum of the subject so that a face plate disposed at aproximal end of the stimulation delivery device abuts, and is locatedexternal to, the punctum, wherein the stimulation delivery deviceincludes a body comprised of a mesh or braid; and applying a stimulationsignal to a tissue of the nasolacrimal drainage system via thestimulation delivery device to induce tearing in the subject.
 41. Themethod of claim 40, wherein the stimulation signal is received via apower receptor at least partially disposed in or on the faceplate. 42.The method of claim 40, further comprising radially expanding at least aportion of the body after the stimulation delivery device has beeninserted through the punctum.
 43. The method of claim 40, whereindelivery of the stimulation signal to the stimulus delivery devicecauses stimulation to be delivered through the mesh to a tissue of anasolacrimal drainage system of the subject.
 44. The method of claim 40,wherein the subject is suffering from dry eye.
 45. A system comprising:a stimulation delivery device, the stimulation delivery deviceincluding: a body extending from a proximal end to a distal end, whereinthe body is configured for insertion through a punctum of a subject; astimulus delivery mechanism positioned between the proximal end and thedistal end; and a faceplate adjacent the proximal end of the body,wherein the faceplate abuts, and is located external to, the punctumwhen the body is inserted through the punctum; and an external device incommunication with the stimulation delivery device, the external deviceconfigured to transfer and/or store data downloaded from the stimulationdelivery device and/or receive and/or deliver programming instructionsto be provided to the stimulation delivery device.
 46. The system ofclaim 45, wherein the external device provides power to the stimulationdelivery device.
 47. The system of claim 45, wherein the external deviceis a smart device.
 48. The system of claim 47, wherein the smart deviceis a mobile device or a computer.
 49. The system of claim 45, whereinthe external device is programmed so that, upon connection of theexternal device with the stimulus delivery device, data is transferredfrom a memory unit of the external device to the stimulus deliverydevice.
 50. The system of claim 45, wherein the external device isprogrammed to collect and store real-time data from the stimulusdelivery device when the stimulus delivery device and the externaldevice are connected to one another.
 51. The system of claim 45, whereinthe external device is programmed for use by a user to power thestimulation delivery device on or off, start or stop a stimulationsignal, change an intensity of a stimulation signal, change a durationof a stimulation signal, change a stimulation pattern of a stimulationsignal, or a combination thereof.